RT info:eu-repo/semantics/article
T1 Withaferin A-silyl ether analogs as potential anti-kinetoplastid agents targeting the programmed cell death
A1 San Nicol´ás Hern´andez, Desir´ee
A1 Bethencourt Estrella, Carlos Javier
A1 L´opez Arencibia, Atteneri
A1 Hernández Álvarez, Eduardo
A1 Sifaoui, Inés
A1 López Bazzocchi, Isabel
A1 Lorenzo Morales, Jacob
A1 Jiménez Díaz, Ignacio Antonio
A1 Piñero Barroso, José Enrique ¡
K1 Leishmaniasis
K1 Chagas disease
K1 Withaferin A
K1 Apoptosis
K1 Autophagy
AB Current therapies of leishmaniasis and Chagas disease, two of the most widespread neglected tropical diseases,have limited efficacy and toxic side effects. In this regard, natural products play an important role in overcomingthe current need for new antiparasitic agents. The present study reports the leishmanicidal and trypanocidalactivities of twenty-four known silyl-ether derivatives of withaferin A. Eleven compounds from this series (4, 7,8, 10, 12, 15, 17, 18, 20, 22 and 25) showed a potent dose-dependent inhibitory effect on the proliferation ofLeishmania amazonensis promastigotes and Trypanosoma cruzi epimastigotes respectively, even higher than thereferences drugs, miltefosine and benznidazole. Among them, the most promising compound, derivative 10,exhibited approximately 34-fold higher leishmanicidal activity and 49-fold higher trypanocidal activitycompared to the reference drugs, as well as lower cytotoxicity. Moreover, compounds 4, 7, 10, 12 and 15 weremore active than the reference drugs against the amastigote forms of L. amazonensis, presenting a high selectivityindex. Assays performed to study the ATP levels, mitochondrial membrane potential, plasma membranepermeability, chromatin condensation, reactive oxygen species and autophagy indicated that these withaferin Asilylanalogs appear to induce events characteristic of apoptosis-like and also autophagy leading to programmedcell death. These findings support the therapeutic potential of withaferin A-related steroids as anti-Leishmaniaand Trypanosoma agents.
YR 2023
FD 2023
LK http://riull.ull.es/xmlui/handle/915/35874
UL http://riull.ull.es/xmlui/handle/915/35874
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 21-dic-2024