Abstract
Leishmaniasis and American trypanosomiasis are parasitic diseases that cause significant clinical, social and economic impact on the population of tropical and subtropical countries. Their current treatment is limited and presents multiple drawbacks, including high toxicity, high cost, lengthy treatment plans, as well as the emergence of resistant species. Therefore, there is a need to find new lead compounds with high potency against parasites and low toxicity in patients. In the present work, the bioguided fractionation of an endemic plant from the Canary Islands, Withania aristata, led to the identification of withanolide-type metabolites (1–3) with leishmanicidal and trypanocidal activities. Compounds 1 and 3 showed a significant dose-dependent inhibition effect on the proliferation of L. amazonensis promastigotes and T. cruzi epimastigotes, higher than the reference drugs, miltefosine and benznidazole, respectively. Moreover, compounds 1–3 were more potent (IC50 0.055–0.663 µM) than the reference drug against the intracellular amastigote stage of L. amazonensis, with a high selectivity index on murine macrophage cells (SI 58.66–216.73). Studies on the mechanism of death showed that the compounds induced programmed cell death or that which was apoptosis-like. The present findings underline the potential of withanolides as novel therapeutic antikinetoplastid agents.
Highlights
Leishmaniasis and American trypanosomiasis (Chagas disease), protozoal diseases, are neglected tropical diseases causing considerable morbidity, affecting millions of people every year worldwide [1].Leishmaniasis is an infectious disease caused by protozoal parasites of the genus Leishmania and is transmitted by the bite of a sand fly belonging to the genera Lutzomyia and Phlebotomus
The hexanes and acetone extracts of the leaves of Withania aristata were evaluated against promastigote forms of L. amazonensis and L. donovani, and on the epimastigote stage of T. cruzi
We have successfully identified three potent and selective withanolides with significant leishmanicidal profiles, and high selectivity indexes for L. amazonensis
Summary
Leishmaniasis and American trypanosomiasis (Chagas disease), protozoal diseases, are neglected tropical diseases causing considerable morbidity, affecting millions of people every year worldwide [1].Leishmaniasis is an infectious disease caused by protozoal parasites of the genus Leishmania and is transmitted by the bite of a sand fly belonging to the genera Lutzomyia and Phlebotomus. Leishmaniasis and American trypanosomiasis (Chagas disease), protozoal diseases, are neglected tropical diseases causing considerable morbidity, affecting millions of people every year worldwide [1]. The treatment of these infections has been ineffective by variable sensitivity between species, toxicity, route of administration, requirement for long courses of administration, resistance, adverse effects and cost [4]. In this sense, natural products from plants are a promising source of novel lead compounds, characterized by unique chemical architectures, pharmacophores and inherent drug-like properties [5]
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