In vitro leishmanicidal activity of monomeric and dimeric naphthoquinones
Introduction
In traditional medicine, many plants have already provided valuable clues for potentially antiparasitic compounds, especially simple quinones, quassinoids, and related naphthoquinones (Iwu et al., 1994, Sepúvelda-Boza and Cassels, 1996). The antiprotozoal activities of plant-derived phenolics have attracted renewed attention since simple naphthoquinones such as plumbagin (Croft et al., 1985) and its dimers were isolated by bioassay-guided fractionation of Pera benensis and used in the treatment of cutaneous leishmanaisis (CL) in Amazonian Bolivia (Fournet et al., 1992). The antiprotozoal activity of hydroxynaphthoquinones has long been established (Hudson et al., 1985, Hudson, 1993). Attention has re-focused on this group of compounds, since a pronounced activity against a range of protozoan parasites, including Plasmodium spp., Theileria, Toxoplasma, Eimeria spp. and against Pneumocystis carinii was documented (Hudson et al., 1991). Many naphthoquinones have been identified as possible lead structures against Leishmania, Trypanosoma or Plasmodium parasites, but the potential usefulness is limited by their cytotoxicity and low bioavailability, pointing to the necessity of optimizing the natural product lead to potentiate its activity and reduce side effects (Sepúvelda-Boza and Cassels, 1996). One of us (Laatsch) has synthesized a panel of new monomeric and dimeric oxygenated naphthoquinones. Here, we report on their inhibitory effects on the extracellular promastigote stage of Leishmania donovani, L. infantum,L. enriettii, and L. major and on the intracellular amastigote stage of L. donovani parasites in comparison with their direct effects on their macrophage host cell and on different human cell lines in in vitro cultures.
Section snippets
Compounds
All compounds were synthesized in the lab of Prof. H. Laatsch, Göttingen, FRG as published and listed in Fig. 1, Fig. 2. The purity of the compounds was determined by high-performance liquid chromatography (HPLC; purity >90%) and nuclear magnetic resonance (NMR) spectroscopy. Pentamidine-isethionate (Rhone–Poulenc Rorer (Abdi et al., 1995)), amphotericin B (Sigma, Deisenhofen, FRG (Neal and Croft, 1984) and sodium stibogluconate (Pentostam®; kindly provided by Dr J. Goldbach, Glaxo Wellcome,
Results and discussion
The in vitro leishmanicidal activity of tested monomeric (Fig. 1) and dimeric (Fig. 2) naphthoquinones against promastigote L. donovani, L. infantum,L. enriettii, L. major, and against intracellular amastigote L. donovani are shown in Table 1 in comparison to pentamidine-isethionate and amphotericin B as antileishmanial reference drugs. Compounds (11) and (14), dimeric naphthoquinones, exhibited the highest toxicity for intracellularly persisting L. donovani parasites with EC50 values of 15.0
Acknowledgements
The authors wish to thank Ulrike Folkens for excellent technical assistance.
References (36)
Coenzyme Q homologs in parasitic protozoa as targets for chemotherapeutic attack
Parasitol. Today
(1994)- et al.
Biological and chemical studies of Pera benensis, a Bolivian plant used in folk medicine as a treatment of cutaneous leishmaniasis
J. Ethnopharmacol.
(1992) - et al.
Site of action of the antimalarial hydroxynaphthoquinone 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80)
Biochem. Pharmacol.
(1992) - et al.
Leishmania mexicana: energy metabolism of amastigotes and promastigotes
Exp. Parasitol.
(1982) Atovaquone — a novel broad-spectrum anti-infective drug
Parasitol. Today
(1993)- et al.
A modified colorimetric assay of macrophage activation for intracellular cytotoxicity against Leishmania parasites
J. Immunol. Methods
(1990) - et al.
Redox cycling of o-naphthoquinones in trypanosomatids
Biochem. Pharmacol.
(1996) - et al.
Handbook of Drugs for Tropical Parasitic Infections
(1995) - et al.
Über die Synthese des Alkannans und anderer Alkylnaphtazine
Liebigs Ann. Chem.
(1939) - et al.
Regioselektive Synthesen von 3,3′-Bijuglon, Marnegakinon, Dianellion, cyclo-Trijuglon, Xyclosporin und Trianelliondurch Phenol/Chinon-Addition
Liebigs Ann. Chem.
(1983)
A study of the differential respiratory burst elicited by promastigote and amastigote Leishmania donovani in murine peritoneal macrophages
Immunology
The activity of plumbagin and other electron carriers against Leishmania dononani and Leishmania mexicana
Ann. Trop. Med. Parasitol.
The activity of hydroxynaphthoquinones against Leishmania donovani
J. Antimicrob. Chemother.
New diospyrin derivatives with improved inhibitory activity towards Ehrlich ascites carcinoma
Med. Sci. Res.
Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity
Parasitology
566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients
Drugs Exp. Clin. Res.
Medicinal plants in the fight against leishmaniasis
Parasitol. Today
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