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with no adequate sanitation&#44; precarious housing conditions and in contact with vectors&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> These diseases cause high morbidity and mortality rates&#44; resulting in physical&#44; economic and social impacts throughout life&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a></p><p id="para0003" class="elsevierStylePara elsevierViewall">Pharmaceutical companies have little interest in financing programs against these diseases&#44; due to the low financial return they receive from these poor populations&#46; However&#44; programs and action plans for the control&#44; elimination and eradication of these diseases have been developed&#44; such as the WHO Sustainable Development Goals program&#44; which aims to end tuberculosis&#44; malaria and NTDs epidemics by 2030&#46; An initiative to eliminate or eradicate 10 of these diseases by 2020 was presented in the WHO Roadmap on neglected tropical diseases and the 2012 London Declaration on Neglected Tropical Diseases&#46; According to WHO&#44; to achieve the objectives of these programs&#44; public investments for the control of NTDs in the years from 2015 to 2020&#44; excluding vector control&#44; totaled an average of &#36;750 million per year&#46; To maintain progress from 2020 to 2030&#44; an additional &#36;460 million per year in investments are needed&#46; Total investments&#44; excluding donated drugs&#44; for the 2015&#8211;2030 period total &#36;34 billion&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0004" class="elsevierStylePara elsevierViewall">One focusof these control programs is the development of new therapeutic agents&#46; However&#44; the small advance in therapies and the high prevalence of NDs are still disproportionate&#46; Despite the development of many compounds&#44; few of them are directed to NDs&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> In this context&#44; NDs caused by parasitic protozoa stand out in studies for the development of new therapeutic compounds&#46; Although these diseases represent serious public health challenges&#44; only a limited panel of drugs is commercially available for clinical applications&#46;</p></span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">The critical situation on Malaria&#44; Chagas Disease and Leishmaniasis treatment</span><p id="para0005" class="elsevierStylePara elsevierViewall">The WHO warns of the increasing number of malaria cases in more than 80 countries and areas with continuous transmission of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> The treatment of malaria&#44; a disease mainly caused by four human <span class="elsevierStyleItalic">Plasmodium</span> spp&#46; &#40;<span class="elsevierStyleItalic">P&#46; falciparum&#44; P&#46; vivax&#44; P&#46; malariae</span> and <span class="elsevierStyleItalic">P&#46; ovale</span>&#41;&#44; has been progressively updated to the use of a combination of drugs&#46; In this case&#44; artemisinin-based combination therapy &#40;ACT&#41; is applied for infections caused by <span class="elsevierStyleItalic">P&#46; falciparum</span> or by chloroquine-resistant strains of <span class="elsevierStyleItalic">P&#46; vivax</span>&#44; or by the use of chloroquine&#44; supplemented with primaquine&#44; for the treatment of chloroquine susceptible <span class="elsevierStyleItalic">P&#46; vivax</span> infections&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><p id="para0006" class="elsevierStylePara elsevierViewall">Chagas disease&#44;caused by the protozoan <span class="elsevierStyleItalic">Trypanosoma cruzi</span>&#44; is endemic in Latin American countries&#44; affecting more than seven million people and causing more than 10&#44;000 deaths per year&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> This infection causes irreversible and chronic damage to the heart&#44; digestive system&#44; and nervous system&#44; with risk factors related to the low socioeconomic status of the affected population&#46; Only two drugs have been approved for the treatment of Chagas disease during the 60s and 70s&#58; nifurtimox&#44; 5-nitrofuran&#44; &#40;Lampit&#8482;&#47;Bayer&#41; and benznidazole&#44; a nitroimidazole &#40;Lafepe and Abarax&#47;Elea&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a></p><p id="para0007" class="elsevierStylePara elsevierViewall">Leishmaniasesare diseases caused by more than 20 species of protozoa belonging to the Leishmania genus&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> These parasites can affect the lining tissues&#44; such as skin and mucous membranes &#40;Cutaneous Leishmaniasis - CL&#41;&#44; and some species can infect internal tissues and organs&#44; such as liver&#44; spleen&#44; and bone marrow&#44; as well as other organs such as kidney and lung&#44; causing visceral leishmaniasis &#40;VL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> The disease is endemic in approximately 98 countries&#44; especially in Latin America&#44; East Africa and Southeast Asia&#44; with 350 million people under risk of contracting the infection&#46; The estimated incidence rate is 1&#46;5 million new cases per year&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> Since 1940s until now&#44; pentavalent antimonials &#40;meglumine antimoniate and sodium stibogluconate&#41; are considered the main drugs used to treat all clinical forms of leishmaniasis&#44; especially in the New World&#46;</p><p id="para0008" class="elsevierStylePara elsevierViewall">These three groups of parasitic infections share a serious problem&#44; the low availability of alternative treatments&#46; Current treatment for these diseases is questionable and requires continuous monitoring&#46; In addition&#44; only a small portion of the infected population has access to these therapies&#46; Futhermore&#44; clinically approved drugs are expensive and toxic&#44; need long-term administration and can induce the arise ofresistant strains&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">In general&#44; the treatment of these diseases showed little progress in the recent decades&#46; For Chagas disease treatment&#44; the use of benznidazole in children aged 2 to 12 years was approved by the US Food and Drug Administration &#40;FDA&#41; only in 2017&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> In 2014&#44; the repositioning of miltefosine&#44; initially developed for the treatment of breast cancer&#44; was approved for the treatment of leishmaniasis&#44; being currently the only oral medication available for this group of diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> The use of tafenoquine for the radical cure of malaria caused by <span class="elsevierStyleItalic">P&#46; vivax</span> was approved by the FDA in July 2018&#44; being the first global drug for this indication in 60 years&#46; In August 2018 its use for malaria prophylaxis was also approved&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> In 2020&#44; FDA approved the intravenous use of artesunate in U&#46;S&#46; for the treatment of severe malaria followed by a full course of oral antimalarial treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> In addition to these few important advances&#44; the adverse effects and high toxicity that these drugs currently used present&#44; make the need for the search for new therapies for these diseases even greater&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Insights into naphthoquinones as potential drugs to treat infection <span class="elsevierStyleItalic">Plasmodium spp&#46;&#44; Trypanosoma cruzi</span> and <span class="elsevierStyleItalic">Leishmania spp&#46;</span></span><p id="para0010" class="elsevierStylePara elsevierViewall">Different strategies have been used for the search of new drugs for the treatment of these diseases&#44; among them the research and use of natural products and their derivatives&#44; mainly secondary metabolites&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Natural products play an important role as source of compounds for new therapies&#46; In this context&#44; quinones are molecules of great interest in medicinal chemistry due to its spectrum of biological activity and chemical properties&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Quinones are organic substances derived from natural aromatic metabolites found in several plant families&#44; as well as in fungi&#44; algae and bacteria&#46; This group of compounds includes benzoquinones&#44; anthraquinones and naphthoquinones&#46;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a></p><p id="para0011" class="elsevierStylePara elsevierViewall">Among the natural naphthoquinones&#44; lapachol &#40;2-hydroxy-3-&#40;3&#8242;-methyl-2-butenyl&#41;&#8722;1&#44;4-naphthoquinone&#41; stands out&#46; This molecule is known since 1882 and identified since then as a constituent of several plant species of the families Bignoniaceae&#44; Verbenaceae and Proteaceae&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> The greatest occurrence is in the heartwood of the trunk of species of the genus Tabebuia&#44; belonging to the family Bignoniaceae&#44; popularly known as <span class="elsevierStyleItalic">ipes</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> Lapachol has been tested in the past as an alternative in the treatment of solid tumors due to its anti-cancer properties&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> A range of biological effects of lapachol have been established which include analgesic&#44; antiviral&#44; antioxidant&#44; antimicrobial&#44; anti-inflammatory&#44; fungicide and antiparasitic activities&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> Due to low toxicity&#44; lapachol has become a good prototype for the development of synthetic naphthoquinones with interesting biological effects&#44; often with equally low toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a></p><p id="para0012" class="elsevierStylePara elsevierViewall">The antiparasitic activity of lapachol and other naphthoquinones has already been demonstrated&#44; as previously reviewed&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> In addition&#44; other natural naphthoquinones are also notable for to their antiparasitic properties among them&#58; &#945;-lapachone&#44; &#946;-lapachone&#44; lawsone&#44; juglone and plumbagin&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Several other studies have demonstrated the activity of these naphthoquinones against <span class="elsevierStyleItalic">Leishmania</span> spp&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleItalic">Plasmodium</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> and <span class="elsevierStyleItalic">T&#46; cruzi</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a></p><p id="para0013" class="elsevierStylePara elsevierViewall">Supported by ChEMBL Database <span class="elsevierStyleItalic">in vitro</span> results against <span class="elsevierStyleItalic">Leishmania</span> spp&#46;&#44; <span class="elsevierStyleItalic">Plasmodium</span> spp&#46; and <span class="elsevierStyleItalic">T&#46; cruzi</span>&#44; six naphthoquinones were selected according to structural similarity&#44; as shown in the plot on anti-parasitic activity &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#46; Among these&#44; two compounds are natural sources&#160; &#40;&#945;-lapachone and &#946;-lapachone&#41; and four are synthetic derivatives&#58; 2&#44;2-dimethylspiro&#91;3H-benzo&#91;f&#93;&#91;1&#93;benzofuran-9&#44;2&#8242;-oxirane&#93;&#8722;4-one&#44; 2&#44;2-dimethylspiro&#91;3&#44;4&#44;6&#44;7&#44;8&#44;9-hexahydrobenzo&#91;g&#93;chromene-10&#44;2&#8242;-oxirane&#93;&#8722;5-one&#44; 2&#44;2-dimethylspiro&#91;3&#44;4-dihydrobenzo&#91;h&#93;chromene-6&#44;2&#8242;-oxirane&#93;&#8722;5-one and epoxy-&#945;-lapachone&#46; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a> shows that &#945;-lapachone&#44; &#946;-lapachone and epoxy-&#945;-lapachone have been the subject of careful studies against these parasites and the number of <span class="elsevierStyleItalic">in vitro</span> studies on the determination of IC<span class="elsevierStyleInf">50</span> values stands out&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><elsevierMultimedia ident="fig0002"></elsevierMultimedia><p id="para0014" class="elsevierStylePara elsevierViewall">The toxicity of &#946;-lapachone has led to the study of synthetic and semi-synthetic derivatives which may avoid this disadvantage&#46;<a class="elsevierStyleCrossRef" href="#bib0043"><span class="elsevierStyleSup">43</span></a> This review examines epoxy-&#945;-lapachone &#40;ELAP&#41; in which an epoxide ring is introduced into the quinoid center of &#945;-lapachone&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a></p></span></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Epoxy-&#945;-lapachone</span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Synthesis and chemical characterization</span><p id="para0015" class="elsevierStylePara elsevierViewall">Epoxy-&#945;-lapachone &#40;2&#44;2-Dimethyl-3&#44;4-dihydro-spiro&#91;2H-naphtho&#91;2&#44;3-b&#93;pyran-10&#44;2&#8242;-oxirane&#93;&#8722;5&#40;10H&#41;-one&#41;&#44; ELAP&#44; molecular weight 256&#46;3&#160;g&#47;mol and molecular formula C<span class="elsevierStyleInf">16</span>H<span class="elsevierStyleInf">16</span>O<span class="elsevierStyleInf">3</span>&#44; synthesized by the reaction of &#945;-lapachone with an ethereal solution of diazomethane&#44; the first spiro-oxirane derived from a <span class="elsevierStyleItalic">p</span>-quinone to be reported&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> This mechanistic consideration resulted in obtaining ELAP that maintained the parasiticidal activity of its precursor&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Antiparasitic activity</span><p id="para0016" class="elsevierStylePara elsevierViewall">ELAP activity was assessed against three protozoan species&#58; <span class="elsevierStyleItalic">Trypanosoma cruzi&#44; Leishmania</span> spp&#46; and <span class="elsevierStyleItalic">Plasmodium falciparum</span>&#44; causative agents of Chagas disease&#44; leishmaniasis and malaria&#44; respectively&#46; The summary of the main results of <span class="elsevierStyleItalic">in vitro</span> ELAP assays is shown in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0017" class="elsevierStylePara elsevierViewall">The effect of ELAP on the viability of intracellular epimastigotes&#44; trypomastigotes and amastigotes of <span class="elsevierStyleItalic">T&#46; cruzi</span> was assessed&#46; ELAP showed high activity against epimastigote forms &#40;Dm28c strain&#41;&#44; eliminating all parasites within 72&#160;h &#40;DL<span class="elsevierStyleInf">50</span> &#60; 3&#46;1&#160;&#956;M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a> The compound showed the highest activity against this parasite form &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;3&#160;&#956;M&#41; in the series of tested oxiranes&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> ELAP affected the viability of 100&#37; of epimastigote forms when tested in concentrations of 3&#46;1&#160;&#956;M&#44; 12&#46;5&#160;&#956;M and 50 &#956;M&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a></p><p id="para0018" class="elsevierStylePara elsevierViewall">ELAP showed a lower IC<span class="elsevierStyleInf">50</span> value &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;0&#46;05&#160;&#956;M&#41; than epoxymethyl-lawsone &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;13&#160;&#956;M&#41;&#44; an oxirane derived from 2-hydroxy-1&#44;4-naphthoquinone &#40;lawsone&#41; after 72&#160;h of exposure&#46; Both molecules showed lower IC<span class="elsevierStyleInf">50</span> values than benznidazole &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;11&#46;5&#160;&#956;M&#41;&#44; the drug of choice for the treatment of Chagas disease&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a></p><p id="para0019" class="elsevierStylePara elsevierViewall">Their effects on trypomastigote and intracellular amastigote forms of the Y and Colombian strains of <span class="elsevierStyleItalic">T&#46; cruzi</span>&#44; known for their different infectious profiles&#44; were assessed&#46; This study demonstrated that 75&#160;&#956;M of the compound has affected the viability of both strains&#58; 97&#37; of strain Y and 84&#37; of Colombian strain&#46; ELAP activity against intracellular amastigotes inVERO cells infected was higher &#40;96&#46;4&#37; for strain Y&#44; and 95&#46;0&#37; for Colombian strain&#41; than to the human macrophages infected &#40;85&#46;6&#37; strain Y and 71&#46;9&#37; Colombian strain&#41;&#46; Interestingly&#44; results of these assays suggest a preferential <span class="elsevierStyleItalic">in vitro</span> order of ELAP activity against the three <span class="elsevierStyleItalic">T&#46; cruzi</span> forms&#58; epimastigotes &#62; trypomastigotes &#62; intracellular amastigotes&#46;<a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a></p><p id="para0020" class="elsevierStylePara elsevierViewall">Leishmanicidal activity of ELAP was evaluated against <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">V&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis</span> and <span class="elsevierStyleItalic">L</span>&#46; &#40;<span class="elsevierStyleItalic">L</span>&#46;&#41; <span class="elsevierStyleItalic">amazonensis</span>&#44; two of the main causative species of CL in the New World&#46; Promastigote assays showed that ELAP was able to significantly decrease the number of promastigotes after 24&#160;h of exposure&#44; compared to the control&#44; indicating a similar IC<span class="elsevierStyleInf">50</span> value &#40;37&#46;0&#160;&#177;&#160;0&#46;4&#160;&#956;M&#41; for both parasite species&#46; A higher effect of ELAP against these forms in 48&#160;h of exposure indicates that the activity is time- and dose-dependent&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> The effect of ELAP against intracellular amastigote forms was also investigated and a reduction in the endocytic index values for <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">V&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis</span> &#40;491&#46;1&#160;&#177;&#160;40 to 21&#46;0&#160;&#177;&#160;2&#41; and for <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> &#40;290&#46;0&#160;&#177;&#160;30 to 6&#46;0&#160;&#177;&#160;0&#46;8&#41; was observed&#44; demonstrating the ability of the compound to cross the macrophage cell membrane and affect the parasite&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> In addition&#44; it was noted that ELAP is able to induce changes in the mitochondrial membrane potential of the parasite&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p><p id="para0021" class="elsevierStylePara elsevierViewall">A study using BALB&#47;c mice infected with <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> demonstrated that ELAP &#40;0&#46;44&#160;mM&#41; administered subcutaneously in the dorsal region was able to reduce the size of paw lesions to 18&#37; six weeks after treatment compared to untreated animals group &#40;30&#46;8&#160;&#177;&#160;2&#46;6&#160;mm<span class="elsevierStyleSup">3</span>&#41; and animals treated with meglumine antimoniate &#40;MA&#41;&#44; &#40;28&#46;3&#160;&#177;&#160;1&#46;5&#160;mm<span class="elsevierStyleSup">3</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p><p id="para0022" class="elsevierStylePara elsevierViewall">ELAP and 17 other compounds derived from quinones were also tested on the 3D7 strain of <span class="elsevierStyleItalic">P&#46; falciparum</span> present in erythrocytes &#40;100 to 0&#46;14&#160;&#956;g &#47; mL&#41;&#46; The results indicated that ELAP is the most active compound against this parasite&#44; presenting the lowest IC<span class="elsevierStyleInf">50</span> value &#40;3&#46;71&#160;&#956;M&#41;&#44; followed by another oxirane compound derived from a tetrachlorobenzoquinone whose IC<span class="elsevierStyleInf">50</span> value was 3&#46;95&#160;&#956;M&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Combination therapy</span><p id="para0023" class="elsevierStylePara elsevierViewall">Combination therapy has been the basis for the treatment of several infectious diseases&#44; such as malaria&#44; tuberculosis&#44; HIV&#47;AIDS&#44; and its use has gradually been expanded to NTDs&#44; such as leishmaniasis and Chagas disease&#46;<a class="elsevierStyleCrossRef" href="#bib0051"><span class="elsevierStyleSup">51</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0052"><span class="elsevierStyleSup">52</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0053"><span class="elsevierStyleSup">53</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0054"><span class="elsevierStyleSup">54</span></a> This approach has several advantages&#44; such as increased efficacy&#44; reduced dose and treatment time&#44; lower incidence of adverse effects&#44; better patient adherence to treatment&#44; and improved cost-effectiveness&#46; In addition&#44; this approach reduces the possibility of resistant parasite selection&#46;<a class="elsevierStyleCrossRef" href="#bib0051"><span class="elsevierStyleSup">51</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0054"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">55</span></a></p><p id="para0024" class="elsevierStylePara elsevierViewall">The combination of naphthoquinones and their derivatives with other compounds have been tested in other studies as an alternative to the conventional treatment of leishmaniasis&#46; Among them&#44; atovaquone presented leishmanicidal effects <span class="elsevierStyleItalic">in vivo</span> when combined with pentavalent antimonials on <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">donovani</span> as complement to the conventional treatment of VL&#46;<a class="elsevierStyleCrossRef" href="#bib0056"><span class="elsevierStyleSup">56</span></a> Although <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">infantum</span> promastigotes showed resistance to atovaquone when subjected to strain selection &#40;after the fifth pressure&#41;&#44; further studies may confirm that the use of atovaquone in combination with approved drugs may still be an alternative for the treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0057"><span class="elsevierStyleSup">57</span></a> Plumbagin&#44; a naphthoquinone obtained from the roots of <span class="elsevierStyleItalic">Plumbago capensis</span>&#44; was tested in a double combination with acriflavine&#44; saponin or trifluralin&#44; for the treatment of BALB&#47;c mice infected by <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">major</span>&#46; Combination therapy resulted in the total elimination of parasites in the lesions and significantly reduced the parasitic burden on the liver and spleen&#44; compared to monotherapy and untreated controls&#46;<a class="elsevierStyleCrossRef" href="#bib0058"><span class="elsevierStyleSup">58</span></a></p><p id="para0025" class="elsevierStylePara elsevierViewall">Interestingly&#44; ELAP activity was more effective when the treatment was performed in combination with MA compared to monotherapy&#46; The combination of MA&#47;ELAP &#40;3&#58;1&#41; caused a 98&#37; reduction in the <span class="elsevierStyleItalic">in vitro</span> endocytic index of murine peritoneal macrophages infected with <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span>&#46; The treatment of BALB&#47;c mice infected with the same species resulted in a reduction of 62&#37; of the size lesion of the paw&#44; and decrease of 97&#37; in parasitic load in the paw&#46;<a class="elsevierStyleCrossRef" href="#bib0059"><span class="elsevierStyleSup">59</span></a> These results indicate that the combination of these compounds with pentavalent antimonials may represent a promising approach to the management of CL treatment&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Toxicity</span><p id="para0026" class="elsevierStylePara elsevierViewall">The added value of toxicity tests during research and development of new drugs&#44; represents a major contribution to the understanding of the dose-response relationship as well as to the extrapolation of data obtained in research with animal models for humans&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">60</span></a> In this way&#44; a set of <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> tests has been conducted to establish the safety range for research on ELAP as a potential drug&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">in vitro</span> cytotoxicity of ELAP was assayed on VERO cells &#40;ATCC&#44; CRL-1586&#41;&#44; a fibroblast cell line in the kidney of the African green monkey &#40;<span class="elsevierStyleItalic">Cercopithecus aethiops</span>&#41;&#46; ELAP was shown to be the least cytotoxic compound &#40;CD<span class="elsevierStyleInf">50</span>&#62; 50&#160;&#956;M&#41; compared to other tested naphthoquinone derivatives&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a> Lower cytotoxicity and high selectivity &#40;CC<span class="elsevierStyleInf">50</span>&#47;IC<span class="elsevierStyleInf">50</span>&#41; were found for ELAP &#40;CC<span class="elsevierStyleInf">50</span>&#62; 50&#160;&#956;M and IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;3&#160;&#956;M&#41; when compared to &#946;-lapachone &#40;CC<span class="elsevierStyleInf">50</span> &#60;3&#46;1&#160;&#956;M and IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;0&#46;9&#160;&#956;M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> ELAP presented no toxicity to bone marrow-derived macrophage lineage&#44; and also to VERO cells as noted in previous studies&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a></p><p id="para0028" class="elsevierStylePara elsevierViewall">ELAP was tested on a human fibroblast cell line &#40;MRC-5&#41; and human macrophages&#46; The assays with MRC-5&#44; for 48&#160;h of interaction in the concentrations of 1&#46;56&#160;&#956;g&#47;mL to 100&#160;&#956;g&#47;mL&#44; presented a low IC<span class="elsevierStyleInf">50</span> value on this strain &#40;IC<span class="elsevierStyleInf">50</span>&#62; 100&#160;&#956;M&#41; and a significant selectivity index &#40;IS&#62; 27&#41;&#44; when compared to the other compounds tested&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> Tests over human macrophages from peripheral blood for 24 and 48&#160;h&#44; showed no effects on the viability of this cell type at tested concentrations &#40;25&#160;&#956;M and 75&#160;&#956;M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a></p><p id="para0029" class="elsevierStylePara elsevierViewall">The effects of ELAP &#40;1&#46;9&#160;&#956;M&#47;kg&#47;day&#41; in the organs of healthy BALB&#47;c mice were also investigated&#44; which allowed to evaluate the nature of the damage that these compounds may cause at high doses&#46; Heart tissue was most affected by ELAP with intense necrosis&#44; degeneration of cardiac fibers and mononuclear infiltrates&#46;<a class="elsevierStyleCrossRef" href="#bib0061"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Mechanism of action on the protozoan parasites</span><p id="para0030" class="elsevierStylePara elsevierViewall">The pharmacological activity of a drug is directly related to its chemical structure&#44; which guides the interaction with the parasite&#39;s binding site&#46; It is well known that an important structural feature for the biological activity of &#945;-lapachone is the presence of the C ring as well as the strong influence of the redox center&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> Through structural changes in the &#945;-lapachone molecule&#44; several compounds were synthesized&#44; including ELAP&#44; by the introduction of the oxirane ring in the quinonoid center&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a></p><p id="para0031" class="elsevierStylePara elsevierViewall">To elucidate the mechanism of action of ELAP&#44; as well as other derivatives&#44; previous data about the activities of its precursors are important&#46; Differently from other quinones&#44; whose mechanism of action is related to the formation of ROS from the redox cycle of the ortho- and para-quinonoid centers&#44; the activity of &#945;-lapachone and its derivatives has not been shown to be involved in the ROS production&#44; especially in the <span class="elsevierStyleItalic">T&#46; cruzi</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0062"><span class="elsevierStyleSup">62</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0063"><span class="elsevierStyleSup">63</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">65</span></a> It has also been proposed that the trypanocidal activity of these compounds would be due to another mechanism&#44; possibly related to the presence of the oxirane ring of ELAP&#44; since this modification resulted in increased cytotoxic effect on the parasite&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a></p><p id="para0032" class="elsevierStylePara elsevierViewall">A possible mechanism for ELAP action is an inhibition of serine proteases of the parasite&#44; observed in epimastigote forms of <span class="elsevierStyleItalic">T&#46; cruzi</span> and in both promastigotes and amastigotes of <span class="elsevierStyleItalic">L&#46; &#40;L&#46;&#41; amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a> Furthermore&#44; in silico studies indicate that ELAP is able to bind oligopeptidase B &#40;OPB&#41; from <span class="elsevierStyleItalic">L&#46; &#40;L&#46;&#41; amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p><p id="para0033" class="elsevierStylePara elsevierViewall">Although the mode of action of ELAP on biochemical pathways of <span class="elsevierStyleItalic">P&#46; falciparum</span> is still unknown&#44; it is possible to hypothesize such actions based on the findings in <span class="elsevierStyleItalic">T&#46; cruzi&#44; L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> and <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">V&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis</span>&#46; There is evidence that ELAP acts as a serine protease inhibitor of <span class="elsevierStyleItalic">P&#46; falciparum</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> but nothing has been described about the effect of the compound on the multiplication or any other event in the parasite&#39;s biological cycle&#46; However&#44; it is plausible that its action interferes with several points in the parasite&#39;s physiology&#44; since proteolytic activity&#44; including the numerous isoforms and homologues of serine proteases&#44; is essential for the survival of organisms&#46;<a class="elsevierStyleCrossRef" href="#bib0066"><span class="elsevierStyleSup">66</span></a></p><p id="para0034" class="elsevierStylePara elsevierViewall">In addition to these biological actions described for ELAP&#44; it is also possible to conjecture its role in the modulation of cells or components of the immune system&#44; as discussed based on the reactive potential of its molecular structure&#46;<a class="elsevierStyleCrossRef" href="#bib0059"><span class="elsevierStyleSup">59</span></a> Thus&#44; it is possible that ELAP acts directly over the parasite cell or indirectly by the modulation of mediator&#39;s expression of the immune response&#44; as proposed for &#945;-lapachone and &#946;-lapachone&#46; For both isomers&#44; properties of blocking the expression of pro-inflammatory cytokines such as interleukin IL-1b&#44; IL-6 and tumor necrosis factor have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0067"><span class="elsevierStyleSup">67</span></a></p><p id="para0035" class="elsevierStylePara elsevierViewall">A recent in silico study demonstrated the potential of ELAP to act on different enzymes from <span class="elsevierStyleItalic">Leishmania</span> spp&#46; based on previous results in the literature related to the activity of other naphthoquinones in different parasites&#58; &#946;-lapachone in <span class="elsevierStyleItalic">Coccidioides posadasii</span>&#59; 2-phenoxy-1&#44;4-naphthoquinone in <span class="elsevierStyleItalic">T&#46; brucei</span>&#59; Buparvaquone in <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">mexicana</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0068"><span class="elsevierStyleSup">68</span></a> Docking results showed that ELAP is able to form stable complexes with favorable binding energy with key enzymes of the metabolic pathway such as glycolysis &#40;glyceraldehyde 3-phosphate dehydrogenase&#58; &#8722;8&#46;5&#160;kcal&#47;mol to &#8722;8&#46;3&#160;kcal&#47; mol&#41;&#59; electron transport chain &#40;Cytochrome C&#58; &#8722;10&#46;0&#160;kcal&#47;mol to &#8722;9&#46;0&#160;kcal&#47;mol&#41;&#59; and lipid metabolism &#40;lanosterol C-14 demethylase&#58; &#8722;8&#46;4&#160;kcal&#47;mol to &#8722;8&#46;2&#160;kcal&#47;mol&#41; of <span class="elsevierStyleItalic">Leishmania</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0068"><span class="elsevierStyleSup">68</span></a></p></span></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Conclusion and remarks</span><p id="para0036" class="elsevierStylePara elsevierViewall">More effective drugs with low toxicity for the treatment of NDs are needed&#44; which has encouraged studies with natural products and their derivatives as potential sources&#46; Thereby&#44; the results presented in this review indicate safety and efficacy of ELAP as a promising drug for use in the treatment of different parasitic diseases&#44; such as malaria&#44; Chagas disease and leishmaniasis&#46; The accumulated knowledge in the past 19 years about the successful tests with ELAP compound in preclinical trials for the treatment of these NTDs motivated the present review study&#44; highlighting a potential multi-target drug for these parasites&#44; based on its notable chemical property and the ability to act as an oxidizing or dehydrogenating agent&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; <span class="elsevierStyleItalic">in vitro</span> assays and studies with infection models&#44; aiming to establish the efficacy and understanding of the mode of action is more advanced for tegumentary leishmaniasis compared to those related to malaria and Chagas disease&#46; Available expertise on the <span class="elsevierStyleItalic">Leishmania</span> spp&#46; infection model shows evidence that supports the potential of ELAP as a multi-directed compound capable of interrupting the network interactions of important parasite enzymes&#44; representing a promising approach for the treatment of these parasitic diseases&#46; These data certainly point to the possibility of combination therapy of ELAP with MA for the treatment of CL&#44;<a class="elsevierStyleCrossRef" href="#bib0059"><span class="elsevierStyleSup">59</span></a> since different chemical structures and mechanisms of action of both drugs may interfere on multiple physiological targets&#44; obtaining a synergistic or additive effect on the parasites&#46;<a class="elsevierStyleCrossRef" href="#bib0068"><span class="elsevierStyleSup">68</span></a></p><p id="para0038" class="elsevierStylePara elsevierViewall">Furthermore&#44; the combination of ELAP and pentavalent antimonials might represent a therapeutic line with a better balance between effectiveness and toxicity&#44; preventing or minimizing some known adverse effects of current therapy&#46; In addition&#44; this approach can avoid the appearance of refractory strains&#46; In this context&#44; there is the possibility to study the use of ELAP combined with traditional therapies for other NDs&#46;</p><p id="para0039" class="elsevierStylePara elsevierViewall">Aiming to improve the effects on parasites and reduce the incidence of adverse effects&#44; there is also the alternative to incorporate ELAP in drug delivery systems based on micro and nanotechnology&#46; This approach can increase stability and bioavailability as well as promote a more efficient release of the compound&#46;<a class="elsevierStyleCrossRef" href="#bib0069"><span class="elsevierStyleSup">69</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">70</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0071"><span class="elsevierStyleSup">71</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0072"><span class="elsevierStyleSup">72</span></a></p><p id="para0040" class="elsevierStylePara elsevierViewall">Data gathered here show evidence that studies with <span class="elsevierStyleItalic">Leishmania</span> spp&#46; provide the necessary information for conducting a high technology readiness level &#40;TRL&#41;&#47; manufacturing readiness level &#40;MRL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0073"><span class="elsevierStyleSup">73</span></a> sinceproofs-of-concept have have already been completed&#46; Thus&#44; the set of results gathered available to the scientific community indicate ELAP as a viable product worthy of development as a drug&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "titulo" => "Introduction"
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            0 => array:2 [
              "identificador" => "sec0002"
              "titulo" => "Neglected diseases general considerations"
            ]
            1 => array:2 [
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              "titulo" => "The critical situation on Malaria&#44; Chagas Disease and Leishmaniasis treatment"
            ]
            2 => array:2 [
              "identificador" => "sec0004"
              "titulo" => "Insights into naphthoquinones as potential drugs to treat infection Plasmodium spp&#46;&#44; Trypanosoma cruzi and Leishmania spp&#46;"
            ]
          ]
        ]
        3 => array:3 [
          "identificador" => "sec0005"
          "titulo" => "Epoxy-&#945;-lapachone"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "Synthesis and chemical characterization"
            ]
            1 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Antiparasitic activity"
            ]
            2 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "Combination therapy"
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            3 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Toxicity"
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              "identificador" => "sec0010"
              "titulo" => "Mechanism of action on the protozoan parasites"
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          "identificador" => "sec0011"
          "titulo" => "Conclusion and remarks"
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          "titulo" => "Funding"
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        6 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2022-09-22"
    "fechaAceptado" => "2023-01-13"
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            0 => "Naphthoquinone"
            1 => "Epoxy-&#945;-lapachone"
            2 => "Treatment"
            3 => "Leishmaniasis"
            4 => "Chagas disease"
            5 => "Malaria"
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    "resumen" => array:1 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Natural products and their derivatives have been sources of search and research for new drugs for the treatment of neglected diseases&#46; Naphthoquinones&#44; a special group of quinones&#44; are products of natural metabolites with a wide spectrum of biological activities and represent a group of interesting molecules for new therapeutic propositions&#46; Among these compounds&#44; lapachol stands out as a molecule from the heartwood of <span class="elsevierStyleItalic">Tabebuia</span> sp&#46; whose structural changes resulted in compounds considered promising&#44; such as epoxy-&#945;-lapachone &#40;ELAP&#41;&#46; The biological activity of ELAP has been demonstrated&#44; so far&#44; for parasitic protozoa such as <span class="elsevierStyleItalic">Leishmania</span> spp&#46;&#44; <span class="elsevierStyleItalic">Trypanosoma cruzi</span> and <span class="elsevierStyleItalic">Plasmodium</span> spp&#46;&#44; species causing diseases needing new drug development and adequate health policy&#46; This work gathers <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> studies on these parasites&#44; as well as the toxicity profile&#44; and the probable mechanisms of action elucidated until then&#46; The potential of ELAP-based technology alternatives for a further drug is discussed here&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Naphthoquinone anti-parasitic activity plot based on experimental assays&#46;</span> The compounds &#945;-lapachone &#40;A&#41;&#44; &#946;-lapachone &#40;B&#41;&#44; 2&#44;2-dimethylspiro&#91;3H-benzo&#91;f&#93;&#91;1&#93;benzofuran-9&#44;2&#8242;-oxirane&#93;-4-one &#40;C&#41;&#44; 2&#44;2-dimethylspiro&#91;3&#44;4&#44;6&#44;7&#44;8&#44;9-hexahydrobenzo&#91;g&#93;chromene-10&#44;2&#8242;-oxirane&#93;-5-one &#40;D&#41;&#44; 2&#44;2-dimethylspiro&#91;3&#44;4-dihydrobenzo&#91;h&#93;chromene-6&#44;2&#8242;-oxirane&#93;-5-one &#40;E&#41; and epoxy-&#945; -lapachone &#40;F&#41; were selected according to structural similarity &#40;&#62;50&#37;&#41; using the ChEMBL Database &#40;<span class="elsevierStyleInterRef" id="interref0001" href="https://www.ebi.ac.uk/chembl/">https&#58;&#47;&#47;www&#46;ebi&#46;ac&#46;uk&#47;chembl&#47;</span>&#41;&#46; This analysis shows the activities of these molecules against to <span class="elsevierStyleItalic">Plasmodium</span> spp&#46; &#40;purple circle&#41;&#44; <span class="elsevierStyleItalic">Trypanosoma cruzi</span> &#40;yellow circle&#41;&#44; and <span class="elsevierStyleItalic">Leishmania</span> spp&#46; &#40;green circle&#41; based on IC<span class="elsevierStyleInf">50</span> values normalized &#40;pChEMBL value&#41;&#46; The circle sizes show a predict values of permeability &#40;ALogP&#41; of these compounds&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Predicted epoxy-&#945;-lapachone regions interactions with amino acid residues of the active site of trypanosomatid proteases&#46;</span> Epoxy-&#945;-lapachone &#40;2&#44;3-Dihydro-3&#44;3-dimethylspiro&#91;1H-4-oxanthracene-5&#44;2&#8242;-oxiran&#93;&#8722;10&#40;5H&#41;-one&#41; is formed by an aromatic ring &#40;A&#41;&#44; a central six-membered ring &#40;B&#41; and a ring with two methyl groups &#40;C&#41;&#46; The chiral center being the C12 atom&#44; which is also part of the three-membered epoxide ring&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> CID&#58; 12&#44;000&#44;280&#59; molecular formula&#58;C<span class="elsevierStyleInf">16</span>H<span class="elsevierStyleInf">16</span>O<span class="elsevierStyleInf">3</span> and molecular mass&#58; 256&#46;3&#160;g&#47;mol&#46; Epoxy-&#945;-lapachone regions interactions with amino acid residues of cysteine-proteinase &#40;green&#41; of <span class="elsevierStyleItalic">Trypanosoma cruzi</span><a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a> and serine-proteinase &#40;orange&#41; of <span class="elsevierStyleItalic">Leishmania</span> &#40;<span class="elsevierStyleItalic">Leishmania</span>&#41; <span class="elsevierStyleItalic">amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Species</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Evolutive form</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Biological Activity</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0004"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">References</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0005"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Tripanosoma cruzi</span></td><a name="en0006"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="top">Epimastigote &#40;strain Dm28c&#41;</td><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">LD<span class="elsevierStyleInf">50</span> &#60; 3&#46;1&#160;&#181;M - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;3&#160;&#181;M - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Growth inhibition &#40;100&#37;&#41; - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0016"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Epimastigote &#40;strain Y&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0019"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;0&#46;05&#160;&#181;M - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Tripomastigote &#40;strain Y&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Growth inhibition &#40;97&#37;&#41; - 72h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a></td></tr><tr title="table-row"><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Tripomastigote &#40;strain Colombiana&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Growth inhibition &#40;84&#37;&#41; - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Intracellular amastigote &#40;strain Y&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleBold">Human macrophages&#58;</span>Growth inhibition &#40;85&#46;6&#37;&#41; &#8211; 72&#160;h<span class="elsevierStyleBold">VERO Cell&#58;</span>Growth inhibition &#40;96&#46;4&#37;&#41; &#8211; 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0034"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleBold">Human macrophages&#58;</span>Growth inhibition &#40;71&#46;9&#37;&#41; &#8211; 72&#160;h<span class="elsevierStyleBold">VERO Cell&#58;</span>Growth inhibition &#40;95&#46;0&#37;&#41; &#8211; 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Leishmania</span> &#40;<span class="elsevierStyleItalic">Leishmania</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> &#40;strain MHOM&#47;BR&#47;73&#47;LTB0016&#41;<span class="elsevierStyleItalic">Leishmania</span> &#40;<span class="elsevierStyleItalic">Viannia</span>&#41; <span class="elsevierStyleItalic">braziliensis</span> &#40;strain MCAN&#47;BR&#47;1998&#47;R619&#41;</td><a name="en0038"></a><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleBold">IC<span class="elsevierStyleInf">50</span>&#58;</span><span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis&#58;</span> 37&#46;0&#160;&#177;&#160;0&#46;4&#160;&#181;M &#8211; 24&#160;h<span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis&#58;</span> 37&#46;0&#160;&#177;&#160;0&#46;4&#160;&#181;M &#8211; 24 h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="top"><a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a></td></tr><tr title="table-row"><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Intracellular amastigote&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0043"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><span class="elsevierStyleBold">Human macrophages - IE&#58;</span><span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis&#58;</span> 21&#46;0&#160;&#177;&#160;2<span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis&#58;</span> 6&#46;0&#160;&#177;&#160;0&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="top"><span class="elsevierStyleItalic">Plasmodium falciparum</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Erythrocytic form&#40;strain 3D7&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="top">IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;3&#46;71&#160;&#956;M - 48 h&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec1"
          "bibliografiaReferencia" => array:73 [
            0 => array:3 [
              "identificador" => "bib0001"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://www.who.int/health-topics/neglected-tropical-diseases#tab=tab_1">https&#58;&#47;&#47;www&#46;who&#46;int&#47;health-topics&#47;neglected-tropical-diseases&#35;tab&#61;tab&#95;1</a> &#40;accessed 09&#46;16&#46;22&#41;&#46;"
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0002"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://apps.who.int/iris/bitstream/handle/10665/311689/9789241515450-eng.pdf?ua=1">https&#58;&#47;&#47;apps&#46;who&#46;int&#47;iris&#47;bitstream&#47;handle&#47;10665&#47;311689&#47;9789241515450-eng&#46;pdf&#63;ua&#61;1</a> &#40;acessed 09&#46;16&#46;22&#41;&#46;"
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0003"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://apps.who.int/iris/handle/10665/255011">https&#58;&#47;&#47;apps&#46;who&#46;int&#47;iris&#47;handle&#47;10665&#47;255011</a> &#40;accessed 09&#46;16&#46;22&#41;&#46;"
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0004"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://apps.who.int/iris/handle/10665/152781">https&#58;&#47;&#47;apps&#46;who&#46;int&#47;iris&#47;handle&#47;10665&#47;152781</a> &#40;accessed 09&#46;16&#46;22&#41;"
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drugs and vaccines in the 21st century for neglected diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46;L&#46;G&#46; Ferreira"
                            1 => "A&#46;D&#46; Andricopulo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet Infect Dis"
                        "fecha" => "2019"
                        "volumen" => "1"
                        "paginaInicial" => "125"
                        "paginaFinal" => "127"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0006"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="http://apps.who.int/iris/bitstream/handle/10665/275867/9789241565653-eng.pdf">http&#58;&#47;&#47;apps&#46;who&#46;int&#47;iris&#47;bitstream&#47;handle&#47;10665&#47;275867&#47;9789241565653-eng&#46;pdf</a> &#40;accessed 16&#46;09&#46;22&#41;&#46;"
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0007"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://www.who.int/chagas/en/">https&#58;&#47;&#47;www&#46;who&#46;int&#47;chagas&#47;en&#47;</a> &#40;accessed 09&#46;16&#46;22&#41;&#46;"
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0008"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sosa-Estani S&#46; Clinical and pharmacological profile of benznidazole for treatment of Chagas disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;M&#46; Kratz"
                            1 => "F&#46; Garcia Bournissen"
                            2 => "C&#46;J&#46; Forsyth"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/17512433.2018.1509704"
                      "Revista" => array:6 [
                        "tituloSerie" => "Expert Rev Clin Pharmacol"
                        "fecha" => "2018"
                        "volumen" => "11"
                        "paginaInicial" => "943"
                        "paginaFinal" => "957"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30111183"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0009"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://apps.who.int/iris/handle/10665/44412">https&#58;&#47;&#47;apps&#46;who&#46;int&#47;iris&#47;handle&#47;10665&#47;44412</a> &#40;accessed 09&#46;16&#46;22&#41;"
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A historical overview of the classification&#44; evolution&#44; and dispersion of Leishmania parasites and sandflies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Akhoundi"
                            1 => "K&#46; Kuhls"
                            2 => "A&#46; Cannet"
                            3 => "J&#46; Vot&#253;pka"
                            4 => "P&#46; Marty"
                            5 => "P&#46; Delaunay"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "PLoS Negl Trop Dis"
                        "fecha" => "2016"
                        "volumen" => "10"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0011"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tegumentary and visceral leishmaniases in Brazil&#58; emerging anthropozoonosis and possibilities for their control"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;C&#46;D&#46;A&#46; Marzochi"
                            1 => "K&#46;B&#46;F&#46; Marzochi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cad Saude Publica"
                        "fecha" => "1994"
                        "volumen" => "10"
                        "paginaInicial" => "S359"
                        "paginaFinal" => "S375"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0012"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Leishmaniasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "B&#46;L Herwaldt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(98)10178-2"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1999"
                        "volumen" => "354"
                        "paginaInicial" => "1191"
                        "paginaFinal" => "1199"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10513726"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0013"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Benznidazole approved for Chagas disease in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "K&#46; Traynor"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2146/news170065"
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Health Syst Pharm"
                        "fecha" => "2017"
                        "volumen" => "74"
                        "paginaInicial" => "1519"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28947517"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0014"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Why miltefosine&#8212;a life-saving drug for leishmaniasis&#8212;Is unavailable to people who need it the most"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "T&#46; Sunyoto"
                            1 => "J&#46; Potet"
                            2 => "M&#46; Boelaert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "BMJ Glob Health"
                        "fecha" => "2018"
                        "volumen" => "3"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tafenoquine&#58; first global approval"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "J&#46;E Frampton"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s40265-018-0979-2"
                      "Revista" => array:5 [
                        "tituloSerie" => "Drugs&#46;"
                        "fecha" => "2018"
                        "volumen" => "78"
                        "paginaInicial" => "1517"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30229442"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0016"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://www.fda.gov/news-events/press-announcements/fda-approves-only-drug-us-treat-severe-malaria">https&#58;&#47;&#47;www&#46;fda&#46;gov&#47;news-events&#47;press-announcements&#47;fda-approves-only-drug-us-treat-severe-malaria</a> &#40;accessed 20&#46;09&#46;22&#41;&#46;"
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0017"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The World Medicines situation&#44; 2011"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "WHO 2011"
                          "etal" => false
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:3 [
                        "fecha" => "2011"
                        "editorial" => "Tradicional medicines&#58; global situation&#44; issues and challenges"
                        "editorialLocalizacion" => "Geneva"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0018"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quinone chemistry and toxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "T&#46;J&#46; Monks"
                            1 => "R&#46;P&#46; Hanzlik"
                            2 => "G&#46;M&#46; Cohen"
                            3 => "D&#46; Ross"
                            4 => "D&#46;G&#46; Graham"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0041-008x(92)90273-u"
                      "Revista" => array:6 [
                        "tituloSerie" => "Toxicol Appl Pharmacol"
                        "fecha" => "1992"
                        "volumen" => "112"
                        "paginaInicial" => "2"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1733045"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0019"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Naphthoquinones&#58; biological properties and synthesis of lawsone and derivates-a structured review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46;I&#46;L&#46; L&#243;pez"
                            1 => "S&#46;D&#46;N&#46; Flores"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Vitae"
                        "fecha" => "2014"
                        "volumen" => "21"
                        "paginaInicial" => "248"
                        "paginaFinal" => "258"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ricerche Sull Acido Lapacico"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "E Paterno"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Gazz Chim Ital"
                        "fecha" => "1882"
                        "volumen" => "12"
                        "paginaInicial" => "337"
                        "paginaFinal" => "339"
                      ]
                    ]
                  ]
                ]
              ]
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            20 => array:3 [
              "identificador" => "bib0021"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The constitution of lapachol and its derivatives&#46; The struture of the amylene chain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46;C&#46; Hooker"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Chem Soc"
                        "fecha" => "1896"
                        "volumen" => "69"
                        "paginaInicial" => "1355"
                        "paginaFinal" => "1381"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0022"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Um panorama atual da qu&#237;mica e da farmacologia de naftoquinonas&#44; com &#234;nfase na &#946;-lapachona e derivados"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;N&#46; da Silva"
                            1 => "V&#46;F&#46; Ferreira"
                            2 => "M&#46;C&#46;B&#46;V&#46; de Souza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Qu&#237;m Nova"
                        "fecha" => "2003"
                        "volumen" => "26"
                        "paginaInicial" => "407"
                        "paginaFinal" => "416"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0023"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Traditional medicinal plants for the treatment and prevention of human parasitic diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Willcox"
                            1 => "B&#46; Gilbert"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Ethnopharmacol"
                        "fecha" => "2009"
                        "paginaInicial" => "199e208"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0024"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recognition and evaluation of lapachol as an antitumor agent"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "K&#46;V&#46; Rao"
                            1 => "T&#46;J&#46; McBride"
                            2 => "J&#46;J&#46; Oleson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "1968"
                        "volumen" => "28"
                        "paginaInicial" => "1952"
                        "paginaFinal" => "1954"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lapachol and lapachone analogs&#58; a journey of two decades of patent research &#40;1997-2016&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Hussain"
                            1 => "I&#46;R&#46; Green"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/13543776.2017.1339792"
                      "Revista" => array:6 [
                        "tituloSerie" => "Expert Opin Ther Pat"
                        "fecha" => "2017"
                        "volumen" => "27"
                        "paginaInicial" => "1111"
                        "paginaFinal" => "1121"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28586252"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0026"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">In vitro</span> leishmanicidal activity of monomeric and dimeric naphthoquinones"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "O&#46; Kayser"
                            1 => "A&#46;F&#46; Kiderlen"
                            2 => "H&#46; Laatsch"
                            3 => "S&#46;L&#46; Croft"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0001-706x(00)00078-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Trop"
                        "fecha" => "2000"
                        "volumen" => "76"
                        "paginaInicial" => "131"
                        "paginaFinal" => "138"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10936572"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0027"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Natural naphthoquinones and their derivatives as potential drug molecules against trypanosome parasites"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "R&#46; Rani"
                            1 => "K&#46; Sethi"
                            2 => "S&#46; Kumar"
                            3 => "R&#46;S&#46; Varma"
                            4 => "R&#46; Kumar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Chem Biol Drug Des"
                        "fecha" => "2022"
                        "volumen" => "00"
                        "paginaInicial" => "1"
                        "paginaFinal" => "32"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0028"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antileishmanial activity of lapachol analogues"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46;M&#46;F&#46; Lima"
                            1 => "C&#46;S&#46; Correia"
                            2 => "L&#46;L&#46; Leon"
                            3 => "G&#46; Machado"
                            4 => "M&#46;D&#46;F&#46; Madeira"
                            5 => "A&#46;E&#46;G&#46; Santana"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1590/s0074-02762004000700017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mem Inst Oswaldo Cruz"
                        "fecha" => "2004"
                        "volumen" => "99"
                        "paginaInicial" => "757"
                        "paginaFinal" => "761"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15654435"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0029"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy of lapachol on treatment of cutaneous and visceral leishmaniasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "I&#46;A&#46;C&#46; Ara&#250;jo"
                            1 => "R&#46;C&#46; de Paula"
                            2 => "C&#46;L&#46; Alves"
                            3 => "K&#46;F&#46; Faria"
                            4 => "M&#46;M&#46; Oliveira"
                            5 => "G&#46;G&#46; Mendes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.exppara.2019.02.013"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Parasitol"
                        "fecha" => "2019"
                        "volumen" => "199"
                        "paginaInicial" => "67"
                        "paginaFinal" => "73"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30797783"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "30"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites&#58; synthesis of novel &#945;-and nor-&#945;-lapachone-based 1&#44;2&#44;3-triazoles by copper-catalyzed azide&#8211;alkyne cycloaddition"
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                          "autores" => array:6 [
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                            1 => "C&#46; Pinto Mdo"
                            2 => "J&#46;S&#46; Lanza"
                            3 => "M&#46;N&#46; Melo"
                            4 => "R&#46;L&#46; do Monte-Neto"
                            5 => "I&#46;M&#46; de Melo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejmech.2013.02.038"
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                        "tituloSerie" => "Eur J Med Chem"
                        "fecha" => "2013"
                        "volumen" => "63"
                        "paginaInicial" => "523"
                        "paginaFinal" => "530"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23535320"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0031"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence for leishmanicidal activity of the naphthoquinone derivative epoxy-&#945;-lapachone"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Souza-Silva"
                            1 => "S&#46;B&#46; do Nascimento"
                            2 => "S&#46;C&#46; Bourguignon"
                            3 => "B&#46;A&#46; Pereira"
                            4 => "P&#46;F&#46; Carneiro"
                            5 => "W&#46;S&#46; da Silva"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.exppara.2014.10.002"
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                        "tituloSerie" => "Exp Parasitol"
                        "fecha" => "2014"
                        "volumen" => "147"
                        "paginaInicial" => "81"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25307687"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0032"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of plumbagin and its derivative as potential modulators of redox thiol metabolism of <span class="elsevierStyleItalic">Leishmania</span> parasite"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
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                            2 => "M&#46; Das"
                            3 => "V&#46;K&#46; Dubey"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "tituloSerie" => "Parasitol Res"
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                        "volumen" => "110"
                        "paginaInicial" => "341"
                        "paginaFinal" => "348"
                      ]
                    ]
                  ]
                ]
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            32 => array:3 [
              "identificador" => "bib0033"
              "etiqueta" => "33"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "In silico&#44; <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> evaluation of natural Bignoniaceous naphthoquinones in comparison with atovaquone targeting the selection of potential antimalarial candidates"
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                            2 => "L&#46;C&#46;R&#46; de Souza"
                            3 => "C&#46;A&#46; Tagliati"
                            4 => "A&#46;B&#46; de Oliveira"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "Toxicol Appl Pharmacol"
                        "fecha" => "2020"
                        "volumen" => "401"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0034"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent"
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                        0 => array:2 [
                          "etal" => true
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                            3 => "M&#46;N&#46; Menezes"
                            4 => "J&#46;R&#46; Reys"
                            5 => "A&#46;E&#46; Santana"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3109/14756366.2014.958083"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Enzyme Inhib Med Chem"
                        "fecha" => "2015"
                        "volumen" => "30"
                        "paginaInicial" => "615"
                        "paginaFinal" => "621"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25431148"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "35"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Blood shizonticidal activities of phenazines and naphthoquinoidal compounds against <span class="elsevierStyleItalic">Plasmodium falciparum in vitro</span> and in mice malaria studies"
                      "autores" => array:1 [
                        0 => array:2 [
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                            2 => "P&#46;F&#46; Carneiro"
                            3 => "G&#46;A&#46; Jardim"
                            4 => "I&#46;M&#46; de Melo"
                            5 => "E&#46;N&#46; da Silva J&#250;nior"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Mem Inst Oswaldo Cruz"
                        "fecha" => "2014"
                        "volumen" => "109"
                        "paginaInicial" => "546"
                        "paginaFinal" => "552"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25099332"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antimalarial naphthoquinones&#46; Synthesis via click chemistry&#44; <span class="elsevierStyleItalic">in vitro</span> activity&#44; docking to PfDHODH and SAR of lapachol-based compounds"
                      "autores" => array:1 [
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                            3 => "L&#46;F&#46; Soares"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Eur J Med Chem"
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                        "volumen" => "145"
                        "paginaInicial" => "191"
                        "paginaFinal" => "205"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29324340"
                            "web" => "Medline"
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                      ]
                    ]
                  ]
                ]
              ]
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            36 => array:3 [
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Synthesis and antimalarial activity of quinones and structurally-related oxirane derivatives"
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                        0 => array:2 [
                          "etal" => true
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                      ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Eur J Med Chem"
                        "fecha" => "2016"
                        "volumen" => "108"
                        "paginaInicial" => "134"
                        "paginaFinal" => "140"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26638044"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0038"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">Trypanosoma cruzi</span>&#58; activities of lapachol and &#945;- and &#946;-lapachone derivatives against epimastigote and trypomastigote forms"
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                        0 => array:2 [
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                            1 => "R&#46;A&#46; Tapia"
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                      ]
                    ]
                  ]
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                    0 => array:2 [
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                        "tituloSerie" => "Bioorg Med Chem"
                        "fecha" => "2008"
                        "volumen" => "16"
                        "paginaInicial" => "668"
                        "paginaFinal" => "674"
                        "link" => array:1 [
                          0 => array:2 [
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                      "titulo" => "New oxirane derivatives of 1&#44; 4-naphthoquinones and their evaluation against <span class="elsevierStyleItalic">T&#46; cruzi</span> epimastigote forms"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Synthesis and anti-<span class="elsevierStyleItalic">Trypanosoma cruzi</span> activity of derivatives from nor-lapachones and lapachones"
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                          "etal" => true
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                            3 => "R&#46;F&#46; Menna-Barreto"
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                            5 => "F&#46; de Assis Lopes"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "paginaFinal" => "5038"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18378461"
                            "web" => "Medline"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Studies of trypanocidal &#40;inhibitory&#41; power of naphthoquinones&#58; evaluation of quantum chemical molecular descriptors for structure&#8211;activity relationships"
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                        "tituloSerie" => "Eur J Med Chem"
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                        "paginaInicial" => "2238"
                        "paginaFinal" => "2246"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18276039"
                            "web" => "Medline"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Trypanocidal activity and redox potential of heterocyclic- and 2-hydroxy-naphthoquinones"
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                            3 => "L&#46;R&#46; Freitas"
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                        "paginaFinal" => "2048"
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                0 => array:2 [
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                      "titulo" => "Natural and synthetic naphthoquinones as potential anti-infective agents"
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                        "tituloSerie" => "Curr Top Med Chem"
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                        "paginaFinal" => "2069"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34525920"
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              "identificador" => "bib0044"
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                    0 => array:2 [
                      "titulo" => "2&#44;3-Dihydro-3&#44;3-dimethylspiro-&#91;1H-4-oxanthracene-5&#44;2&#8217;-oxiran&#93;-10&#40;5H&#41;-one"
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                            5 => "M&#46;C&#46; de Souza"
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                        "tituloSerie" => "Acta Crystallogr"
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                        "volumen" => "58"
                        "paginaInicial" => "560"
                        "paginaFinal" => "562"
                      ]
                    ]
                  ]
                ]
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                    0 => array:2 [
                      "titulo" => "Compendium of Chemical Terminology"
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                      "titulo" => "Oxyrane derivative of &#945;-lapachone is potent growth inhibitor of <span class="elsevierStyleItalic">Trypanosoma cruzi</span> epimastigote forms"
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                        "paginaFinal" => "433"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16596415"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16725327"
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                    0 => array:2 [
                      "titulo" => "<span class="elsevierStyleItalic">Trypanosoma cruzi</span>&#58; insights into naphthoquinone effects on growth and proteinase activity"
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                      "titulo" => "Drug combinations for visceral leishmaniasis"
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            55 => array:3 [
              "identificador" => "bib0056"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Activity of oral atovaquone alone and in combination with antimony in experimental visceral leishmaniasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46;W&#46; Murray"
                            1 => "J&#46; Hariprashad"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Antimicrob Agents Ch"
                        "fecha" => "1996"
                        "volumen" => "40"
                        "paginaInicial" => "586"
                        "paginaFinal" => "587"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0057"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterisation of atovaquone resistance in <span class="elsevierStyleItalic">Leishmania infantum</span> promastigotes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Cauchetier"
                            1 => "P&#46;M&#46; Loiseau"
                            2 => "J&#46; Lehman"
                            3 => "D&#46; Rivollet"
                            4 => "J&#46; Fleury"
                            5 => "A&#46; Astier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0020-7519(02)00065-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Parasitol"
                        "fecha" => "2002"
                        "volumen" => "32"
                        "paginaInicial" => "1043"
                        "paginaFinal" => "1051"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12076633"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0058"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combination and monotherapy of <span class="elsevierStyleItalic">Leishmania major</span> infection in BALB&#47;c mice using plant extracts and herbicides"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;A&#46; Makwali"
                            1 => "F&#46;M&#46; Wanjala"
                            2 => "J&#46;C&#46; Kaburi"
                            3 => "J&#46; Ingonga"
                            4 => "W&#46;W&#46; Byrum"
                            5 => "C&#46;O Anjili"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Vector Borne Dis"
                        "fecha" => "2012"
                        "volumen" => "49"
                        "paginaInicial" => "123"
                        "paginaFinal" => "130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23135005"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0059"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The combination therapy of meglumine antimoniate and oxiranes &#40;epoxy-&#945;-lapachone and epoxymethyl-lawsone&#41; enhance the leishmanicidal effect in mice infected by <span class="elsevierStyleItalic">Leishmania</span> &#40;<span class="elsevierStyleItalic">Leishmania</span>&#41; <span class="elsevierStyleItalic">amazonensis</span>"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;F&#46; Gon&#231;alves-Oliveira"
                            1 => "F&#46; Souza-Silva"
                            2 => "L&#46;M&#46; de Castro C&#244;rtes"
                            3 => "L&#46;B&#46; Veloso"
                            4 => "B&#46;A&#46; Santini Pereira"
                            5 => "L&#46; Cysne-Finkelstein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ijpddr.2019.08.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Parasitol Drugs Drug Resist"
                        "fecha" => "2019"
                        "volumen" => "10"
                        "paginaInicial" => "101"
                        "paginaFinal" => "108"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31430693"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Toxicology in the drug discovery and development process"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;A&#46; Dorato"
                            1 => "L&#46;A&#46; Buckley"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Current Protocols in Pharmacol"
                        "fecha" => "2006"
                        "volumen" => "32"
                        "paginaInicial" => "10&#46;3&#46;1"
                        "paginaFinal" => "10&#46;3&#46;35"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0061"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evidence for tissue toxicity in BALB&#47;c exposed to a long-term treatment with oxiranes compared to meglumine antimoniate"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;F&#46;G&#46; Oliveira"
                            1 => "F&#46; Souza-Silva"
                            2 => "L&#46; Cysne-Finkelstein"
                            3 => "K&#46; Rabelo"
                            4 => "J&#46;F&#46; Amorim"
                            5 => "A&#46;S&#46; Azevedo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:2 [
                        "tituloSerie" => "Biomed Res Int"
                        "fecha" => "2017"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0062"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular mechanisms of quinone cytotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46;J&#46; O&#39;Brien"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/0009-2797(91)90029-7"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chem Biol Interact"
                        "fecha" => "1991"
                        "volumen" => "80"
                        "paginaInicial" => "1"
                        "paginaFinal" => "41"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1913977"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0063"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The metabolism and toxicity of quinones&#44; quinonimines&#44; quinone methides&#44; and quinonethioethers"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46;J&#46; Monks"
                            1 => "D&#46;C&#46; Jones"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Curr Drug Metab"
                        "fecha" => "2002"
                        "volumen" => "3"
                        "paginaInicial" => "425"
                        "paginaFinal" => "438"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0064"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemicals and drugs forming reactive quinone and quinone imine metabolites"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "I&#46; Klop&#269;i&#269;"
                            1 => "M&#46;S&#46; Dolenc"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1021/acs.chemrestox.8b00213"
                      "Revista" => array:6 [
                        "tituloSerie" => "Chem Res Toxicol"
                        "fecha" => "2018"
                        "volumen" => "32"
                        "paginaInicial" => "1"
                        "paginaFinal" => "34"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30500181"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone deriva-tives-eleutherin&#44; alpha lapachone&#44; and beta lapachone"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46; Krishnan"
                            1 => "K&#46;F&#46; Bastow"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0006-2952(00)00437-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Pharmacol"
                        "fecha" => "2000"
                        "volumen" => "60"
                        "paginaInicial" => "1367"
                        "paginaFinal" => "1379"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11008131"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0066"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A critical review on serine protease&#58; key immune manipulator and pathology mediator"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46; Patel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.aller.2016.10.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Allergol Immunopathol &#40;Madr&#41;"
                        "fecha" => "2017"
                        "volumen" => "45"
                        "paginaInicial" => "579"
                        "paginaFinal" => "591"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28236540"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0067"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46;O&#46; Moon"
                            1 => "Y&#46;H&#46; Choi"
                            2 => "N&#46;D&#46; Kim"
                            3 => "Y&#46;M&#46; Park"
                            4 => "G&#46;Y&#46; Kim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Int Immunopharmacol"
                        "fecha" => "2007"
                        "volumen" => "7"
                        "paginaInicial" => "506"
                        "paginaFinal" => "514"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0068"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "In Silico Insights into the mechanism of action of epoxy-&#945;-lapachone and epoxymethyl-lawsone in <span class="elsevierStyleItalic">Leishmania</span> spp"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;F&#46; Peixoto"
                            1 => "A&#46;D&#46;S&#46; Oliveira"
                            2 => "P&#46;Q&#46; Monteiro"
                            3 => "L&#46;F&#46; Gon&#231;alves-Oliveira"
                            4 => "V&#46;V&#46; Andrade-Neto"
                            5 => "V&#46;F&#46; Ferreira"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/molecules26123537"
                      "Revista" => array:5 [
                        "tituloSerie" => "Molecules"
                        "fecha" => "2021"
                        "volumen" => "26"
                        "paginaInicial" => "3537"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34200517"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0069"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intelligent drug-delivery devices based on micro- and nano-technologies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;H&#46; Chi"
                            1 => "K&#46; Clayton"
                            2 => "T&#46;J&#46; Burrow"
                            3 => "R&#46; Lewis"
                            4 => "D&#46; Luciano"
                            5 => "F&#46; Alexis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4155/tde.12.139"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ther Deliv"
                        "fecha" => "2013"
                        "volumen" => "4"
                        "paginaInicial" => "77"
                        "paginaFinal" => "94"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23323782"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nano based drug delivery systems&#58; recent developments and future prospects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;K&#46; Patra"
                            1 => "G&#46; Das"
                            2 => "L&#46;F&#46; Fraceto"
                            3 => "E&#46;V&#46;R&#46; Campos"
                            4 => "M&#46;D&#46;P&#46; Rodriguez-Torres"
                            5 => "L&#46;S&#46; Acosta-Torres"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Nanobiotechnol"
                        "fecha" => "2018"
                        "volumen" => "16"
                        "paginaInicial" => "71"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0071"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nanotechnology applications in drug controlled release"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Simonazzi"
                            1 => "A&#46;G&#46; Cid"
                            2 => "M&#46; Villegas"
                            3 => "A&#46;I&#46; Romero"
                            4 => "S&#46;D&#46; Palma"
                            5 => "J&#46;M&#46; Berm&#250;dez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:5 [
                        "titulo" => "Drug Targeting and Stimuli Sensitive Drug Delivery Systems"
                        "fecha" => "2018"
                        "paginaInicial" => "81"
                        "paginaFinal" => "116"
                        "editorial" => "William Andrew Publishing"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0072"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nanoparticulate drug delivery systems for the treatment of neglected tropical protozoan diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46; Volpedo"
                            1 => "L&#46; Costa"
                            2 => "N&#46; Ryan"
                            3 => "G&#46; Halsey"
                            4 => "A&#46; Satoskar"
                            5 => "S&#46; Oghumu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "J Venom Anim Toxins Incl Trop Dis"
                        "fecha" => "2019"
                        "volumen" => "25"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0073"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "<a target="_blank" href="https://www.excellenting.com/drug_discovery_trl/">https&#58;&#47;&#47;www&#46;excellenting&#46;com&#47;drug&#95;discovery&#95;trl&#47;</a> &#40;accessed 23&#46;12&#46;22&#41;"
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              ]
            ]
          ]
        ]
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Epoxy-α-lapachone (2,2-Dimethyl-3,4-dihydro-spiro[2H-naphtho[2,3-b]pyran-10,2′-oxirane]-5(10H)-one): a promising molecule to control infections caused by protozoan parasites
Juliana Figueiredo Peixotoa, Adriane da Silva Oliveiraa, Luiz Filipe Gonçalves - Oliveiraa, Franklin Souza - Silvab,c, Carlos Roberto Alvesa,
Corresponding author
calves@ioc.fiocruz.br

Corresponding author.
a Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia Molecular e Doenças Endêmicas, Rio de Janeiro, RJ, Brazil
b Fundação Oswaldo Cruz, Centro de Desenvolvimento Tecnológico em Saúde, Rio de Janeiro, RJ, Brazil
c Universidade Iguaçu, Nova Iguaçu, RJ, Brazil
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Predicted epoxy-&#945;-lapachone regions interactions with amino acid residues of the active site of trypanosomatid proteases&#46;</span> Epoxy-&#945;-lapachone &#40;2&#44;3-Dihydro-3&#44;3-dimethylspiro&#91;1H-4-oxanthracene-5&#44;2&#8242;-oxiran&#93;&#8722;10&#40;5H&#41;-one&#41; is formed by an aromatic ring &#40;A&#41;&#44; a central six-membered ring &#40;B&#41; and a ring with two methyl groups &#40;C&#41;&#46; The chiral center being the C12 atom&#44; which is also part of the three-membered epoxide ring&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> CID&#58; 12&#44;000&#44;280&#59; molecular formula&#58;C<span class="elsevierStyleInf">16</span>H<span class="elsevierStyleInf">16</span>O<span class="elsevierStyleInf">3</span> and molecular mass&#58; 256&#46;3&#160;g&#47;mol&#46; Epoxy-&#945;-lapachone regions interactions with amino acid residues of cysteine-proteinase &#40;green&#41; of <span class="elsevierStyleItalic">Trypanosoma cruzi</span><a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a> and serine-proteinase &#40;orange&#41; of <span class="elsevierStyleItalic">Leishmania</span> &#40;<span class="elsevierStyleItalic">Leishmania</span>&#41; <span class="elsevierStyleItalic">amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Introduction</span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Neglected diseases general considerations</span><p id="para0001" class="elsevierStylePara elsevierViewall">Neglected diseases &#40;NDs&#41; affect millions of people worldwide&#44; especially in developing nations&#44; which have little attention from their governments and pharmaceutical companies&#46; The World Health Organization &#40;WHO&#41; has classified 20 of these diseases as neglected tropical diseases &#40;NTDs&#41;&#44; including several infections caused by viruses&#44; bacteria&#44; fungi&#44; and protozoa&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a></p><p id="para0002" class="elsevierStylePara elsevierViewall">NDs mainly affect populations living in conditions of poverty in tropical and subtropical climates&#44; with no adequate sanitation&#44; precarious housing conditions and in contact with vectors&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> These diseases cause high morbidity and mortality rates&#44; resulting in physical&#44; economic and social impacts throughout life&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a></p><p id="para0003" class="elsevierStylePara elsevierViewall">Pharmaceutical companies have little interest in financing programs against these diseases&#44; due to the low financial return they receive from these poor populations&#46; However&#44; programs and action plans for the control&#44; elimination and eradication of these diseases have been developed&#44; such as the WHO Sustainable Development Goals program&#44; which aims to end tuberculosis&#44; malaria and NTDs epidemics by 2030&#46; An initiative to eliminate or eradicate 10 of these diseases by 2020 was presented in the WHO Roadmap on neglected tropical diseases and the 2012 London Declaration on Neglected Tropical Diseases&#46; According to WHO&#44; to achieve the objectives of these programs&#44; public investments for the control of NTDs in the years from 2015 to 2020&#44; excluding vector control&#44; totaled an average of &#36;750 million per year&#46; To maintain progress from 2020 to 2030&#44; an additional &#36;460 million per year in investments are needed&#46; Total investments&#44; excluding donated drugs&#44; for the 2015&#8211;2030 period total &#36;34 billion&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a></p><p id="para0004" class="elsevierStylePara elsevierViewall">One focusof these control programs is the development of new therapeutic agents&#46; However&#44; the small advance in therapies and the high prevalence of NDs are still disproportionate&#46; Despite the development of many compounds&#44; few of them are directed to NDs&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> In this context&#44; NDs caused by parasitic protozoa stand out in studies for the development of new therapeutic compounds&#46; Although these diseases represent serious public health challenges&#44; only a limited panel of drugs is commercially available for clinical applications&#46;</p></span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">The critical situation on Malaria&#44; Chagas Disease and Leishmaniasis treatment</span><p id="para0005" class="elsevierStylePara elsevierViewall">The WHO warns of the increasing number of malaria cases in more than 80 countries and areas with continuous transmission of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a> The treatment of malaria&#44; a disease mainly caused by four human <span class="elsevierStyleItalic">Plasmodium</span> spp&#46; &#40;<span class="elsevierStyleItalic">P&#46; falciparum&#44; P&#46; vivax&#44; P&#46; malariae</span> and <span class="elsevierStyleItalic">P&#46; ovale</span>&#41;&#44; has been progressively updated to the use of a combination of drugs&#46; In this case&#44; artemisinin-based combination therapy &#40;ACT&#41; is applied for infections caused by <span class="elsevierStyleItalic">P&#46; falciparum</span> or by chloroquine-resistant strains of <span class="elsevierStyleItalic">P&#46; vivax</span>&#44; or by the use of chloroquine&#44; supplemented with primaquine&#44; for the treatment of chloroquine susceptible <span class="elsevierStyleItalic">P&#46; vivax</span> infections&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a></p><p id="para0006" class="elsevierStylePara elsevierViewall">Chagas disease&#44;caused by the protozoan <span class="elsevierStyleItalic">Trypanosoma cruzi</span>&#44; is endemic in Latin American countries&#44; affecting more than seven million people and causing more than 10&#44;000 deaths per year&#46;<a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> This infection causes irreversible and chronic damage to the heart&#44; digestive system&#44; and nervous system&#44; with risk factors related to the low socioeconomic status of the affected population&#46; Only two drugs have been approved for the treatment of Chagas disease during the 60s and 70s&#58; nifurtimox&#44; 5-nitrofuran&#44; &#40;Lampit&#8482;&#47;Bayer&#41; and benznidazole&#44; a nitroimidazole &#40;Lafepe and Abarax&#47;Elea&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a></p><p id="para0007" class="elsevierStylePara elsevierViewall">Leishmaniasesare diseases caused by more than 20 species of protozoa belonging to the Leishmania genus&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> These parasites can affect the lining tissues&#44; such as skin and mucous membranes &#40;Cutaneous Leishmaniasis - CL&#41;&#44; and some species can infect internal tissues and organs&#44; such as liver&#44; spleen&#44; and bone marrow&#44; as well as other organs such as kidney and lung&#44; causing visceral leishmaniasis &#40;VL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a> The disease is endemic in approximately 98 countries&#44; especially in Latin America&#44; East Africa and Southeast Asia&#44; with 350 million people under risk of contracting the infection&#46; The estimated incidence rate is 1&#46;5 million new cases per year&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> Since 1940s until now&#44; pentavalent antimonials &#40;meglumine antimoniate and sodium stibogluconate&#41; are considered the main drugs used to treat all clinical forms of leishmaniasis&#44; especially in the New World&#46;</p><p id="para0008" class="elsevierStylePara elsevierViewall">These three groups of parasitic infections share a serious problem&#44; the low availability of alternative treatments&#46; Current treatment for these diseases is questionable and requires continuous monitoring&#46; In addition&#44; only a small portion of the infected population has access to these therapies&#46; Futhermore&#44; clinically approved drugs are expensive and toxic&#44; need long-term administration and can induce the arise ofresistant strains&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">In general&#44; the treatment of these diseases showed little progress in the recent decades&#46; For Chagas disease treatment&#44; the use of benznidazole in children aged 2 to 12 years was approved by the US Food and Drug Administration &#40;FDA&#41; only in 2017&#46;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> In 2014&#44; the repositioning of miltefosine&#44; initially developed for the treatment of breast cancer&#44; was approved for the treatment of leishmaniasis&#44; being currently the only oral medication available for this group of diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> The use of tafenoquine for the radical cure of malaria caused by <span class="elsevierStyleItalic">P&#46; vivax</span> was approved by the FDA in July 2018&#44; being the first global drug for this indication in 60 years&#46; In August 2018 its use for malaria prophylaxis was also approved&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> In 2020&#44; FDA approved the intravenous use of artesunate in U&#46;S&#46; for the treatment of severe malaria followed by a full course of oral antimalarial treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> In addition to these few important advances&#44; the adverse effects and high toxicity that these drugs currently used present&#44; make the need for the search for new therapies for these diseases even greater&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Insights into naphthoquinones as potential drugs to treat infection <span class="elsevierStyleItalic">Plasmodium spp&#46;&#44; Trypanosoma cruzi</span> and <span class="elsevierStyleItalic">Leishmania spp&#46;</span></span><p id="para0010" class="elsevierStylePara elsevierViewall">Different strategies have been used for the search of new drugs for the treatment of these diseases&#44; among them the research and use of natural products and their derivatives&#44; mainly secondary metabolites&#46;<a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> Natural products play an important role as source of compounds for new therapies&#46; In this context&#44; quinones are molecules of great interest in medicinal chemistry due to its spectrum of biological activity and chemical properties&#46;<a class="elsevierStyleCrossRef" href="#bib0018"><span class="elsevierStyleSup">18</span></a> Quinones are organic substances derived from natural aromatic metabolites found in several plant families&#44; as well as in fungi&#44; algae and bacteria&#46; This group of compounds includes benzoquinones&#44; anthraquinones and naphthoquinones&#46;<a class="elsevierStyleCrossRef" href="#bib0019"><span class="elsevierStyleSup">19</span></a></p><p id="para0011" class="elsevierStylePara elsevierViewall">Among the natural naphthoquinones&#44; lapachol &#40;2-hydroxy-3-&#40;3&#8242;-methyl-2-butenyl&#41;&#8722;1&#44;4-naphthoquinone&#41; stands out&#46; This molecule is known since 1882 and identified since then as a constituent of several plant species of the families Bignoniaceae&#44; Verbenaceae and Proteaceae&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">20</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0021"><span class="elsevierStyleSup">21</span></a> The greatest occurrence is in the heartwood of the trunk of species of the genus Tabebuia&#44; belonging to the family Bignoniaceae&#44; popularly known as <span class="elsevierStyleItalic">ipes</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0022"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0023"><span class="elsevierStyleSup">23</span></a> Lapachol has been tested in the past as an alternative in the treatment of solid tumors due to its anti-cancer properties&#46;<a class="elsevierStyleCrossRef" href="#bib0024"><span class="elsevierStyleSup">24</span></a> A range of biological effects of lapachol have been established which include analgesic&#44; antiviral&#44; antioxidant&#44; antimicrobial&#44; anti-inflammatory&#44; fungicide and antiparasitic activities&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a> Due to low toxicity&#44; lapachol has become a good prototype for the development of synthetic naphthoquinones with interesting biological effects&#44; often with equally low toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">25</span></a></p><p id="para0012" class="elsevierStylePara elsevierViewall">The antiparasitic activity of lapachol and other naphthoquinones has already been demonstrated&#44; as previously reviewed&#46;<a class="elsevierStyleCrossRef" href="#bib0026"><span class="elsevierStyleSup">26</span></a> In addition&#44; other natural naphthoquinones are also notable for to their antiparasitic properties among them&#58; &#945;-lapachone&#44; &#946;-lapachone&#44; lawsone&#44; juglone and plumbagin&#46;<a class="elsevierStyleCrossRef" href="#bib0027"><span class="elsevierStyleSup">27</span></a> Several other studies have demonstrated the activity of these naphthoquinones against <span class="elsevierStyleItalic">Leishmania</span> spp&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0028"><span class="elsevierStyleSup">28</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0029"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0032"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleItalic">Plasmodium</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0033"><span class="elsevierStyleSup">33</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0034"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0036"><span class="elsevierStyleSup">36</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> and <span class="elsevierStyleItalic">T&#46; cruzi</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0038"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">40</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0041"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0042"><span class="elsevierStyleSup">42</span></a></p><p id="para0013" class="elsevierStylePara elsevierViewall">Supported by ChEMBL Database <span class="elsevierStyleItalic">in vitro</span> results against <span class="elsevierStyleItalic">Leishmania</span> spp&#46;&#44; <span class="elsevierStyleItalic">Plasmodium</span> spp&#46; and <span class="elsevierStyleItalic">T&#46; cruzi</span>&#44; six naphthoquinones were selected according to structural similarity&#44; as shown in the plot on anti-parasitic activity &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1</a>&#41;&#46; Among these&#44; two compounds are natural sources&#160; &#40;&#945;-lapachone and &#946;-lapachone&#41; and four are synthetic derivatives&#58; 2&#44;2-dimethylspiro&#91;3H-benzo&#91;f&#93;&#91;1&#93;benzofuran-9&#44;2&#8242;-oxirane&#93;&#8722;4-one&#44; 2&#44;2-dimethylspiro&#91;3&#44;4&#44;6&#44;7&#44;8&#44;9-hexahydrobenzo&#91;g&#93;chromene-10&#44;2&#8242;-oxirane&#93;&#8722;5-one&#44; 2&#44;2-dimethylspiro&#91;3&#44;4-dihydrobenzo&#91;h&#93;chromene-6&#44;2&#8242;-oxirane&#93;&#8722;5-one and epoxy-&#945;-lapachone&#46; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2</a> shows that &#945;-lapachone&#44; &#946;-lapachone and epoxy-&#945;-lapachone have been the subject of careful studies against these parasites and the number of <span class="elsevierStyleItalic">in vitro</span> studies on the determination of IC<span class="elsevierStyleInf">50</span> values stands out&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia><elsevierMultimedia ident="fig0002"></elsevierMultimedia><p id="para0014" class="elsevierStylePara elsevierViewall">The toxicity of &#946;-lapachone has led to the study of synthetic and semi-synthetic derivatives which may avoid this disadvantage&#46;<a class="elsevierStyleCrossRef" href="#bib0043"><span class="elsevierStyleSup">43</span></a> This review examines epoxy-&#945;-lapachone &#40;ELAP&#41; in which an epoxide ring is introduced into the quinoid center of &#945;-lapachone&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a></p></span></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Epoxy-&#945;-lapachone</span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Synthesis and chemical characterization</span><p id="para0015" class="elsevierStylePara elsevierViewall">Epoxy-&#945;-lapachone &#40;2&#44;2-Dimethyl-3&#44;4-dihydro-spiro&#91;2H-naphtho&#91;2&#44;3-b&#93;pyran-10&#44;2&#8242;-oxirane&#93;&#8722;5&#40;10H&#41;-one&#41;&#44; ELAP&#44; molecular weight 256&#46;3&#160;g&#47;mol and molecular formula C<span class="elsevierStyleInf">16</span>H<span class="elsevierStyleInf">16</span>O<span class="elsevierStyleInf">3</span>&#44; synthesized by the reaction of &#945;-lapachone with an ethereal solution of diazomethane&#44; the first spiro-oxirane derived from a <span class="elsevierStyleItalic">p</span>-quinone to be reported&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> This mechanistic consideration resulted in obtaining ELAP that maintained the parasiticidal activity of its precursor&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Antiparasitic activity</span><p id="para0016" class="elsevierStylePara elsevierViewall">ELAP activity was assessed against three protozoan species&#58; <span class="elsevierStyleItalic">Trypanosoma cruzi&#44; Leishmania</span> spp&#46; and <span class="elsevierStyleItalic">Plasmodium falciparum</span>&#44; causative agents of Chagas disease&#44; leishmaniasis and malaria&#44; respectively&#46; The summary of the main results of <span class="elsevierStyleItalic">in vitro</span> ELAP assays is shown in <a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0017" class="elsevierStylePara elsevierViewall">The effect of ELAP on the viability of intracellular epimastigotes&#44; trypomastigotes and amastigotes of <span class="elsevierStyleItalic">T&#46; cruzi</span> was assessed&#46; ELAP showed high activity against epimastigote forms &#40;Dm28c strain&#41;&#44; eliminating all parasites within 72&#160;h &#40;DL<span class="elsevierStyleInf">50</span> &#60; 3&#46;1&#160;&#956;M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a> The compound showed the highest activity against this parasite form &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;3&#160;&#956;M&#41; in the series of tested oxiranes&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> ELAP affected the viability of 100&#37; of epimastigote forms when tested in concentrations of 3&#46;1&#160;&#956;M&#44; 12&#46;5&#160;&#956;M and 50 &#956;M&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a></p><p id="para0018" class="elsevierStylePara elsevierViewall">ELAP showed a lower IC<span class="elsevierStyleInf">50</span> value &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;0&#46;05&#160;&#956;M&#41; than epoxymethyl-lawsone &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;13&#160;&#956;M&#41;&#44; an oxirane derived from 2-hydroxy-1&#44;4-naphthoquinone &#40;lawsone&#41; after 72&#160;h of exposure&#46; Both molecules showed lower IC<span class="elsevierStyleInf">50</span> values than benznidazole &#40;IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;11&#46;5&#160;&#956;M&#41;&#44; the drug of choice for the treatment of Chagas disease&#46;<a class="elsevierStyleCrossRef" href="#bib0039"><span class="elsevierStyleSup">39</span></a></p><p id="para0019" class="elsevierStylePara elsevierViewall">Their effects on trypomastigote and intracellular amastigote forms of the Y and Colombian strains of <span class="elsevierStyleItalic">T&#46; cruzi</span>&#44; known for their different infectious profiles&#44; were assessed&#46; This study demonstrated that 75&#160;&#956;M of the compound has affected the viability of both strains&#58; 97&#37; of strain Y and 84&#37; of Colombian strain&#46; ELAP activity against intracellular amastigotes inVERO cells infected was higher &#40;96&#46;4&#37; for strain Y&#44; and 95&#46;0&#37; for Colombian strain&#41; than to the human macrophages infected &#40;85&#46;6&#37; strain Y and 71&#46;9&#37; Colombian strain&#41;&#46; Interestingly&#44; results of these assays suggest a preferential <span class="elsevierStyleItalic">in vitro</span> order of ELAP activity against the three <span class="elsevierStyleItalic">T&#46; cruzi</span> forms&#58; epimastigotes &#62; trypomastigotes &#62; intracellular amastigotes&#46;<a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a></p><p id="para0020" class="elsevierStylePara elsevierViewall">Leishmanicidal activity of ELAP was evaluated against <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">V&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis</span> and <span class="elsevierStyleItalic">L</span>&#46; &#40;<span class="elsevierStyleItalic">L</span>&#46;&#41; <span class="elsevierStyleItalic">amazonensis</span>&#44; two of the main causative species of CL in the New World&#46; Promastigote assays showed that ELAP was able to significantly decrease the number of promastigotes after 24&#160;h of exposure&#44; compared to the control&#44; indicating a similar IC<span class="elsevierStyleInf">50</span> value &#40;37&#46;0&#160;&#177;&#160;0&#46;4&#160;&#956;M&#41; for both parasite species&#46; A higher effect of ELAP against these forms in 48&#160;h of exposure indicates that the activity is time- and dose-dependent&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> The effect of ELAP against intracellular amastigote forms was also investigated and a reduction in the endocytic index values for <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">V&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis</span> &#40;491&#46;1&#160;&#177;&#160;40 to 21&#46;0&#160;&#177;&#160;2&#41; and for <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> &#40;290&#46;0&#160;&#177;&#160;30 to 6&#46;0&#160;&#177;&#160;0&#46;8&#41; was observed&#44; demonstrating the ability of the compound to cross the macrophage cell membrane and affect the parasite&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a> In addition&#44; it was noted that ELAP is able to induce changes in the mitochondrial membrane potential of the parasite&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p><p id="para0021" class="elsevierStylePara elsevierViewall">A study using BALB&#47;c mice infected with <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> demonstrated that ELAP &#40;0&#46;44&#160;mM&#41; administered subcutaneously in the dorsal region was able to reduce the size of paw lesions to 18&#37; six weeks after treatment compared to untreated animals group &#40;30&#46;8&#160;&#177;&#160;2&#46;6&#160;mm<span class="elsevierStyleSup">3</span>&#41; and animals treated with meglumine antimoniate &#40;MA&#41;&#44; &#40;28&#46;3&#160;&#177;&#160;1&#46;5&#160;mm<span class="elsevierStyleSup">3</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p><p id="para0022" class="elsevierStylePara elsevierViewall">ELAP and 17 other compounds derived from quinones were also tested on the 3D7 strain of <span class="elsevierStyleItalic">P&#46; falciparum</span> present in erythrocytes &#40;100 to 0&#46;14&#160;&#956;g &#47; mL&#41;&#46; The results indicated that ELAP is the most active compound against this parasite&#44; presenting the lowest IC<span class="elsevierStyleInf">50</span> value &#40;3&#46;71&#160;&#956;M&#41;&#44; followed by another oxirane compound derived from a tetrachlorobenzoquinone whose IC<span class="elsevierStyleInf">50</span> value was 3&#46;95&#160;&#956;M&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Combination therapy</span><p id="para0023" class="elsevierStylePara elsevierViewall">Combination therapy has been the basis for the treatment of several infectious diseases&#44; such as malaria&#44; tuberculosis&#44; HIV&#47;AIDS&#44; and its use has gradually been expanded to NTDs&#44; such as leishmaniasis and Chagas disease&#46;<a class="elsevierStyleCrossRef" href="#bib0051"><span class="elsevierStyleSup">51</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0052"><span class="elsevierStyleSup">52</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0053"><span class="elsevierStyleSup">53</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0054"><span class="elsevierStyleSup">54</span></a> This approach has several advantages&#44; such as increased efficacy&#44; reduced dose and treatment time&#44; lower incidence of adverse effects&#44; better patient adherence to treatment&#44; and improved cost-effectiveness&#46; In addition&#44; this approach reduces the possibility of resistant parasite selection&#46;<a class="elsevierStyleCrossRef" href="#bib0051"><span class="elsevierStyleSup">51</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0054"><span class="elsevierStyleSup">54</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">55</span></a></p><p id="para0024" class="elsevierStylePara elsevierViewall">The combination of naphthoquinones and their derivatives with other compounds have been tested in other studies as an alternative to the conventional treatment of leishmaniasis&#46; Among them&#44; atovaquone presented leishmanicidal effects <span class="elsevierStyleItalic">in vivo</span> when combined with pentavalent antimonials on <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">donovani</span> as complement to the conventional treatment of VL&#46;<a class="elsevierStyleCrossRef" href="#bib0056"><span class="elsevierStyleSup">56</span></a> Although <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">infantum</span> promastigotes showed resistance to atovaquone when subjected to strain selection &#40;after the fifth pressure&#41;&#44; further studies may confirm that the use of atovaquone in combination with approved drugs may still be an alternative for the treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0057"><span class="elsevierStyleSup">57</span></a> Plumbagin&#44; a naphthoquinone obtained from the roots of <span class="elsevierStyleItalic">Plumbago capensis</span>&#44; was tested in a double combination with acriflavine&#44; saponin or trifluralin&#44; for the treatment of BALB&#47;c mice infected by <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">major</span>&#46; Combination therapy resulted in the total elimination of parasites in the lesions and significantly reduced the parasitic burden on the liver and spleen&#44; compared to monotherapy and untreated controls&#46;<a class="elsevierStyleCrossRef" href="#bib0058"><span class="elsevierStyleSup">58</span></a></p><p id="para0025" class="elsevierStylePara elsevierViewall">Interestingly&#44; ELAP activity was more effective when the treatment was performed in combination with MA compared to monotherapy&#46; The combination of MA&#47;ELAP &#40;3&#58;1&#41; caused a 98&#37; reduction in the <span class="elsevierStyleItalic">in vitro</span> endocytic index of murine peritoneal macrophages infected with <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span>&#46; The treatment of BALB&#47;c mice infected with the same species resulted in a reduction of 62&#37; of the size lesion of the paw&#44; and decrease of 97&#37; in parasitic load in the paw&#46;<a class="elsevierStyleCrossRef" href="#bib0059"><span class="elsevierStyleSup">59</span></a> These results indicate that the combination of these compounds with pentavalent antimonials may represent a promising approach to the management of CL treatment&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Toxicity</span><p id="para0026" class="elsevierStylePara elsevierViewall">The added value of toxicity tests during research and development of new drugs&#44; represents a major contribution to the understanding of the dose-response relationship as well as to the extrapolation of data obtained in research with animal models for humans&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">60</span></a> In this way&#44; a set of <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> tests has been conducted to establish the safety range for research on ELAP as a potential drug&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">in vitro</span> cytotoxicity of ELAP was assayed on VERO cells &#40;ATCC&#44; CRL-1586&#41;&#44; a fibroblast cell line in the kidney of the African green monkey &#40;<span class="elsevierStyleItalic">Cercopithecus aethiops</span>&#41;&#46; ELAP was shown to be the least cytotoxic compound &#40;CD<span class="elsevierStyleInf">50</span>&#62; 50&#160;&#956;M&#41; compared to other tested naphthoquinone derivatives&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a> Lower cytotoxicity and high selectivity &#40;CC<span class="elsevierStyleInf">50</span>&#47;IC<span class="elsevierStyleInf">50</span>&#41; were found for ELAP &#40;CC<span class="elsevierStyleInf">50</span>&#62; 50&#160;&#956;M and IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;3&#160;&#956;M&#41; when compared to &#946;-lapachone &#40;CC<span class="elsevierStyleInf">50</span> &#60;3&#46;1&#160;&#956;M and IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;0&#46;9&#160;&#956;M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> ELAP presented no toxicity to bone marrow-derived macrophage lineage&#44; and also to VERO cells as noted in previous studies&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0049"><span class="elsevierStyleSup">49</span></a></p><p id="para0028" class="elsevierStylePara elsevierViewall">ELAP was tested on a human fibroblast cell line &#40;MRC-5&#41; and human macrophages&#46; The assays with MRC-5&#44; for 48&#160;h of interaction in the concentrations of 1&#46;56&#160;&#956;g&#47;mL to 100&#160;&#956;g&#47;mL&#44; presented a low IC<span class="elsevierStyleInf">50</span> value on this strain &#40;IC<span class="elsevierStyleInf">50</span>&#62; 100&#160;&#956;M&#41; and a significant selectivity index &#40;IS&#62; 27&#41;&#44; when compared to the other compounds tested&#46;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> Tests over human macrophages from peripheral blood for 24 and 48&#160;h&#44; showed no effects on the viability of this cell type at tested concentrations &#40;25&#160;&#956;M and 75&#160;&#956;M&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0031"><span class="elsevierStyleSup">31</span></a></p><p id="para0029" class="elsevierStylePara elsevierViewall">The effects of ELAP &#40;1&#46;9&#160;&#956;M&#47;kg&#47;day&#41; in the organs of healthy BALB&#47;c mice were also investigated&#44; which allowed to evaluate the nature of the damage that these compounds may cause at high doses&#46; Heart tissue was most affected by ELAP with intense necrosis&#44; degeneration of cardiac fibers and mononuclear infiltrates&#46;<a class="elsevierStyleCrossRef" href="#bib0061"><span class="elsevierStyleSup">61</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">Mechanism of action on the protozoan parasites</span><p id="para0030" class="elsevierStylePara elsevierViewall">The pharmacological activity of a drug is directly related to its chemical structure&#44; which guides the interaction with the parasite&#39;s binding site&#46; It is well known that an important structural feature for the biological activity of &#945;-lapachone is the presence of the C ring as well as the strong influence of the redox center&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a> Through structural changes in the &#945;-lapachone molecule&#44; several compounds were synthesized&#44; including ELAP&#44; by the introduction of the oxirane ring in the quinonoid center&#46;<a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a></p><p id="para0031" class="elsevierStylePara elsevierViewall">To elucidate the mechanism of action of ELAP&#44; as well as other derivatives&#44; previous data about the activities of its precursors are important&#46; Differently from other quinones&#44; whose mechanism of action is related to the formation of ROS from the redox cycle of the ortho- and para-quinonoid centers&#44; the activity of &#945;-lapachone and its derivatives has not been shown to be involved in the ROS production&#44; especially in the <span class="elsevierStyleItalic">T&#46; cruzi</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0062"><span class="elsevierStyleSup">62</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0063"><span class="elsevierStyleSup">63</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0064"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">65</span></a> It has also been proposed that the trypanocidal activity of these compounds would be due to another mechanism&#44; possibly related to the presence of the oxirane ring of ELAP&#44; since this modification resulted in increased cytotoxic effect on the parasite&#46;<a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a></p><p id="para0032" class="elsevierStylePara elsevierViewall">A possible mechanism for ELAP action is an inhibition of serine proteases of the parasite&#44; observed in epimastigote forms of <span class="elsevierStyleItalic">T&#46; cruzi</span> and in both promastigotes and amastigotes of <span class="elsevierStyleItalic">L&#46; &#40;L&#46;&#41; amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a> Furthermore&#44; in silico studies indicate that ELAP is able to bind oligopeptidase B &#40;OPB&#41; from <span class="elsevierStyleItalic">L&#46; &#40;L&#46;&#41; amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p><p id="para0033" class="elsevierStylePara elsevierViewall">Although the mode of action of ELAP on biochemical pathways of <span class="elsevierStyleItalic">P&#46; falciparum</span> is still unknown&#44; it is possible to hypothesize such actions based on the findings in <span class="elsevierStyleItalic">T&#46; cruzi&#44; L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">amazonensis</span> and <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">V&#46;</span>&#41; <span class="elsevierStyleItalic">braziliensis</span>&#46; There is evidence that ELAP acts as a serine protease inhibitor of <span class="elsevierStyleItalic">P&#46; falciparum</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0037"><span class="elsevierStyleSup">37</span></a> but nothing has been described about the effect of the compound on the multiplication or any other event in the parasite&#39;s biological cycle&#46; However&#44; it is plausible that its action interferes with several points in the parasite&#39;s physiology&#44; since proteolytic activity&#44; including the numerous isoforms and homologues of serine proteases&#44; is essential for the survival of organisms&#46;<a class="elsevierStyleCrossRef" href="#bib0066"><span class="elsevierStyleSup">66</span></a></p><p id="para0034" class="elsevierStylePara elsevierViewall">In addition to these biological actions described for ELAP&#44; it is also possible to conjecture its role in the modulation of cells or components of the immune system&#44; as discussed based on the reactive potential of its molecular structure&#46;<a class="elsevierStyleCrossRef" href="#bib0059"><span class="elsevierStyleSup">59</span></a> Thus&#44; it is possible that ELAP acts directly over the parasite cell or indirectly by the modulation of mediator&#39;s expression of the immune response&#44; as proposed for &#945;-lapachone and &#946;-lapachone&#46; For both isomers&#44; properties of blocking the expression of pro-inflammatory cytokines such as interleukin IL-1b&#44; IL-6 and tumor necrosis factor have been described&#46;<a class="elsevierStyleCrossRef" href="#bib0067"><span class="elsevierStyleSup">67</span></a></p><p id="para0035" class="elsevierStylePara elsevierViewall">A recent in silico study demonstrated the potential of ELAP to act on different enzymes from <span class="elsevierStyleItalic">Leishmania</span> spp&#46; based on previous results in the literature related to the activity of other naphthoquinones in different parasites&#58; &#946;-lapachone in <span class="elsevierStyleItalic">Coccidioides posadasii</span>&#59; 2-phenoxy-1&#44;4-naphthoquinone in <span class="elsevierStyleItalic">T&#46; brucei</span>&#59; Buparvaquone in <span class="elsevierStyleItalic">L&#46;</span> &#40;<span class="elsevierStyleItalic">L&#46;</span>&#41; <span class="elsevierStyleItalic">mexicana</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0068"><span class="elsevierStyleSup">68</span></a> Docking results showed that ELAP is able to form stable complexes with favorable binding energy with key enzymes of the metabolic pathway such as glycolysis &#40;glyceraldehyde 3-phosphate dehydrogenase&#58; &#8722;8&#46;5&#160;kcal&#47;mol to &#8722;8&#46;3&#160;kcal&#47; mol&#41;&#59; electron transport chain &#40;Cytochrome C&#58; &#8722;10&#46;0&#160;kcal&#47;mol to &#8722;9&#46;0&#160;kcal&#47;mol&#41;&#59; and lipid metabolism &#40;lanosterol C-14 demethylase&#58; &#8722;8&#46;4&#160;kcal&#47;mol to &#8722;8&#46;2&#160;kcal&#47;mol&#41; of <span class="elsevierStyleItalic">Leishmania</span> spp&#46;<a class="elsevierStyleCrossRef" href="#bib0068"><span class="elsevierStyleSup">68</span></a></p></span></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Conclusion and remarks</span><p id="para0036" class="elsevierStylePara elsevierViewall">More effective drugs with low toxicity for the treatment of NDs are needed&#44; which has encouraged studies with natural products and their derivatives as potential sources&#46; Thereby&#44; the results presented in this review indicate safety and efficacy of ELAP as a promising drug for use in the treatment of different parasitic diseases&#44; such as malaria&#44; Chagas disease and leishmaniasis&#46; The accumulated knowledge in the past 19 years about the successful tests with ELAP compound in preclinical trials for the treatment of these NTDs motivated the present review study&#44; highlighting a potential multi-target drug for these parasites&#44; based on its notable chemical property and the ability to act as an oxidizing or dehydrogenating agent&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; <span class="elsevierStyleItalic">in vitro</span> assays and studies with infection models&#44; aiming to establish the efficacy and understanding of the mode of action is more advanced for tegumentary leishmaniasis compared to those related to malaria and Chagas disease&#46; Available expertise on the <span class="elsevierStyleItalic">Leishmania</span> spp&#46; infection model shows evidence that supports the potential of ELAP as a multi-directed compound capable of interrupting the network interactions of important parasite enzymes&#44; representing a promising approach for the treatment of these parasitic diseases&#46; These data certainly point to the possibility of combination therapy of ELAP with MA for the treatment of CL&#44;<a class="elsevierStyleCrossRef" href="#bib0059"><span class="elsevierStyleSup">59</span></a> since different chemical structures and mechanisms of action of both drugs may interfere on multiple physiological targets&#44; obtaining a synergistic or additive effect on the parasites&#46;<a class="elsevierStyleCrossRef" href="#bib0068"><span class="elsevierStyleSup">68</span></a></p><p id="para0038" class="elsevierStylePara elsevierViewall">Furthermore&#44; the combination of ELAP and pentavalent antimonials might represent a therapeutic line with a better balance between effectiveness and toxicity&#44; preventing or minimizing some known adverse effects of current therapy&#46; In addition&#44; this approach can avoid the appearance of refractory strains&#46; In this context&#44; there is the possibility to study the use of ELAP combined with traditional therapies for other NDs&#46;</p><p id="para0039" class="elsevierStylePara elsevierViewall">Aiming to improve the effects on parasites and reduce the incidence of adverse effects&#44; there is also the alternative to incorporate ELAP in drug delivery systems based on micro and nanotechnology&#46; This approach can increase stability and bioavailability as well as promote a more efficient release of the compound&#46;<a class="elsevierStyleCrossRef" href="#bib0069"><span class="elsevierStyleSup">69</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">70</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0071"><span class="elsevierStyleSup">71</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0072"><span class="elsevierStyleSup">72</span></a></p><p id="para0040" class="elsevierStylePara elsevierViewall">Data gathered here show evidence that studies with <span class="elsevierStyleItalic">Leishmania</span> spp&#46; provide the necessary information for conducting a high technology readiness level &#40;TRL&#41;&#47; manufacturing readiness level &#40;MRL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0073"><span class="elsevierStyleSup">73</span></a> sinceproofs-of-concept have have already been completed&#46; Thus&#44; the set of results gathered available to the scientific community indicate ELAP as a viable product worthy of development as a drug&#46;</p></span></span>"
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          "titulo" => "Introduction"
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              "titulo" => "Neglected diseases general considerations"
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              "titulo" => "The critical situation on Malaria&#44; Chagas Disease and Leishmaniasis treatment"
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              "identificador" => "sec0004"
              "titulo" => "Insights into naphthoquinones as potential drugs to treat infection Plasmodium spp&#46;&#44; Trypanosoma cruzi and Leishmania spp&#46;"
            ]
          ]
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          "identificador" => "sec0005"
          "titulo" => "Epoxy-&#945;-lapachone"
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            0 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "Synthesis and chemical characterization"
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            1 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Antiparasitic activity"
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            2 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "Combination therapy"
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              "titulo" => "Toxicity"
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              "titulo" => "Mechanism of action on the protozoan parasites"
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          "titulo" => "Conclusion and remarks"
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          "titulo" => "Funding"
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          "titulo" => "References"
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            1 => "Epoxy-&#945;-lapachone"
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            5 => "Malaria"
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    "resumen" => array:1 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara004" class="elsevierStyleSimplePara elsevierViewall">Natural products and their derivatives have been sources of search and research for new drugs for the treatment of neglected diseases&#46; Naphthoquinones&#44; a special group of quinones&#44; are products of natural metabolites with a wide spectrum of biological activities and represent a group of interesting molecules for new therapeutic propositions&#46; Among these compounds&#44; lapachol stands out as a molecule from the heartwood of <span class="elsevierStyleItalic">Tabebuia</span> sp&#46; whose structural changes resulted in compounds considered promising&#44; such as epoxy-&#945;-lapachone &#40;ELAP&#41;&#46; The biological activity of ELAP has been demonstrated&#44; so far&#44; for parasitic protozoa such as <span class="elsevierStyleItalic">Leishmania</span> spp&#46;&#44; <span class="elsevierStyleItalic">Trypanosoma cruzi</span> and <span class="elsevierStyleItalic">Plasmodium</span> spp&#46;&#44; species causing diseases needing new drug development and adequate health policy&#46; This work gathers <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> studies on these parasites&#44; as well as the toxicity profile&#44; and the probable mechanisms of action elucidated until then&#46; The potential of ELAP-based technology alternatives for a further drug is discussed here&#46;</p></span>"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Naphthoquinone anti-parasitic activity plot based on experimental assays&#46;</span> The compounds &#945;-lapachone &#40;A&#41;&#44; &#946;-lapachone &#40;B&#41;&#44; 2&#44;2-dimethylspiro&#91;3H-benzo&#91;f&#93;&#91;1&#93;benzofuran-9&#44;2&#8242;-oxirane&#93;-4-one &#40;C&#41;&#44; 2&#44;2-dimethylspiro&#91;3&#44;4&#44;6&#44;7&#44;8&#44;9-hexahydrobenzo&#91;g&#93;chromene-10&#44;2&#8242;-oxirane&#93;-5-one &#40;D&#41;&#44; 2&#44;2-dimethylspiro&#91;3&#44;4-dihydrobenzo&#91;h&#93;chromene-6&#44;2&#8242;-oxirane&#93;-5-one &#40;E&#41; and epoxy-&#945; -lapachone &#40;F&#41; were selected according to structural similarity &#40;&#62;50&#37;&#41; using the ChEMBL Database &#40;<span class="elsevierStyleInterRef" id="interref0001" href="https://www.ebi.ac.uk/chembl/">https&#58;&#47;&#47;www&#46;ebi&#46;ac&#46;uk&#47;chembl&#47;</span>&#41;&#46; This analysis shows the activities of these molecules against to <span class="elsevierStyleItalic">Plasmodium</span> spp&#46; &#40;purple circle&#41;&#44; <span class="elsevierStyleItalic">Trypanosoma cruzi</span> &#40;yellow circle&#41;&#44; and <span class="elsevierStyleItalic">Leishmania</span> spp&#46; &#40;green circle&#41; based on IC<span class="elsevierStyleInf">50</span> values normalized &#40;pChEMBL value&#41;&#46; The circle sizes show a predict values of permeability &#40;ALogP&#41; of these compounds&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Predicted epoxy-&#945;-lapachone regions interactions with amino acid residues of the active site of trypanosomatid proteases&#46;</span> Epoxy-&#945;-lapachone &#40;2&#44;3-Dihydro-3&#44;3-dimethylspiro&#91;1H-4-oxanthracene-5&#44;2&#8242;-oxiran&#93;&#8722;10&#40;5H&#41;-one&#41; is formed by an aromatic ring &#40;A&#41;&#44; a central six-membered ring &#40;B&#41; and a ring with two methyl groups &#40;C&#41;&#46; The chiral center being the C12 atom&#44; which is also part of the three-membered epoxide ring&#46;<a class="elsevierStyleCrossRef" href="#bib0044"><span class="elsevierStyleSup">44</span></a> CID&#58; 12&#44;000&#44;280&#59; molecular formula&#58;C<span class="elsevierStyleInf">16</span>H<span class="elsevierStyleInf">16</span>O<span class="elsevierStyleInf">3</span> and molecular mass&#58; 256&#46;3&#160;g&#47;mol&#46; Epoxy-&#945;-lapachone regions interactions with amino acid residues of cysteine-proteinase &#40;green&#41; of <span class="elsevierStyleItalic">Trypanosoma cruzi</span><a class="elsevierStyleCrossRef" href="#bib0048"><span class="elsevierStyleSup">48</span></a> and serine-proteinase &#40;orange&#41; of <span class="elsevierStyleItalic">Leishmania</span> &#40;<span class="elsevierStyleItalic">Leishmania</span>&#41; <span class="elsevierStyleItalic">amazonensis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">50</span></a></p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0001"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Species</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Evolutive form</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0003"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Biological Activity</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0004"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">References</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0005"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="8" align="left" valign="top"><span class="elsevierStyleItalic">Tripanosoma cruzi</span></td><a name="en0006"></a><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="top">Epimastigote &#40;strain Dm28c&#41;</td><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">LD<span class="elsevierStyleInf">50</span> &#60; 3&#46;1&#160;&#181;M - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0046"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">IC<span class="elsevierStyleInf">50</span>&#160;&#61;&#160;1&#46;3&#160;&#181;M - 72 h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><a class="elsevierStyleCrossRef" href="#bib0047"><span class="elsevierStyleSup">47</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\