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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, <i>Withania aristata</i>, led to the identification of withanolide-type metabolites (<b>1</b>&#8722;<b>3</b>) with leishmanicidal and trypanocidal activities. Compounds <b>1</b> and <b>3</b> showed a significant dose-dependent inhibition effect on the proliferation of <i>L. amazonensis</i> promastigotes and <i>T. cruzi</i> epimastigotes, higher than the reference drugs, miltefosine and benznidazole, respectively. Moreover, compounds <b>1</b>&#8722;<b>3</b> were more potent (IC₅₀ 0.055&#8722;0.663 &#181;M) than the reference drug against the intracellular amastigote stage of <i>L. amazonensis,</i> with a high selectivity index on murine macrophage cells (SI 58.66&#8722;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.