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Open AccessArticle

Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death

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Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Avda. Astrofısico Fco. Sanchez, S/N, 38203 La Laguna, Tenerife, Canary Islands, Spain
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Departamento de Obstetricia y Ginecología, Pediatría, Medicina Preventiva y Salud Pública, Toxicología, Medicina Legal y Forense y Parasitología, Universidad de La Laguna, 38200 La Laguna, Tenerife, Spain
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Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Canary Islands, Spain
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Authors to whom correspondence should be addressed.
Pathogens 2019, 8(4), 172; https://doi.org/10.3390/pathogens8040172
Received: 13 September 2019 / Revised: 26 September 2019 / Accepted: 28 September 2019 / Published: 1 October 2019
(This article belongs to the Special Issue Emerging Parasitic Protozoa)
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 (13) 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 13 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. View Full-Text
Keywords: Leishmania; Trypanosoma; Withania aristata; withanolides; apoptosis-like Leishmania; Trypanosoma; Withania aristata; withanolides; apoptosis-like
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López-Arencibia, A.; San Nicolás-Hernández, D.; Bethencourt-Estrella, C.J.; Sifaoui, I.; Reyes-Batlle, M.; Rodríguez-Expósito, R.L.; Rizo-Liendo, A.; Lorenzo-Morales, J.; Bazzocchi, I.L.; Piñero, J.E.; Jiménez, I.A. Withanolides from Withania aristata as Antikinetoplastid Agents through Induction of Programmed Cell Death. Pathogens 2019, 8, 172.

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