Elsevier

Acta Tropica

Volume 76, Issue 2, 18 September 2000, Pages 131-138
Acta Tropica

In vitro leishmanicidal activity of monomeric and dimeric naphthoquinones

https://doi.org/10.1016/S0001-706X(00)00078-4Get rights and content

Abstract

A series of monomeric and dimeric naphthoquinones with potential for treatment of Leishmania infections was identified in vitro using both a direct cytotoxicity assay against extracellular promastigotes of Leishmania donovani, Leishmania infanturn,Leishmania enriettii, and Leishmania major and a test against intracellular amastigote L. donovani residing within murine macrophages. Several naphthoquinones proved to be active at concentrations in the microgram range (EC50 0.9–17.0 μg/ml). When tested against a panel of human cancer cell lines (KB, SKMel, A549, MDA) and murine bone marrow culture-derived macrophages (BMMΦ) as mammalian host cell controls, compounds with anti-Leishmania-activity showed moderate (EC50>25 μg/ml) to pronounced (EC50<10 μg/ml) toxic effects.

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.

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