RT info:eu-repo/semantics/article
T1 Multi-target withaferin-A analogues as promising anti-kinetoplastid agents through the programmed cell death
A1 Jiménez Díaz, Ignacio Antonio
A1 San Nicolás-Hernández, Desir´ée
A1 Hernández-Álvarez, Eduardo
A1 Bethencourt Estrella, Carlos J.
A1 López-Arencibia, Atteneri
A1 Sifaoui, Ines
A1 López Bazzocchi, Isabel
A1 Lorenzo Morales, Jacob
A2 Química Orgánica
K1 Withaferin A analogues
K1 Leishmaniasis
K1 Chagas disease
K1 Chemotherapy
K1 Apoptosis-like
K1 Autophagy
AB Leishmaniasis and Chagas disease, two of the most prevalent neglected tropical diseases, are a world healthproblem. The harsh reality of these infective diseases is the absence of effective and safe therapies. In thisframework, natural products play an important role in overcoming the current need to development new antiparasitic agents. The present study reports the synthesis, antikinetoplastid screening, mechanism study offourteen withaferin A derivatives (2-15). Nine of them (2-6, 8-10 and 12) showed a potent dose-dependentinhibitory effect on the proliferation of Leishmania amazonensis and L. donovani promastigotes and Trypanosoma cruzi epimastigotes with IC50 values ranging from 0.19 to 24.01 µM. Outstandingly, the fully acetylatedderivative 10 (4,27-diacetylwithaferin A) was the most potent compound showing IC50 values of 0.36, 2.82 and0.19 µM against L. amazonensis, L. donovani and T. cruzi, respectively. Furthermore, analogue 10 exhibitedapproximately 18 and 36-fold greater antikinetoplastid activity, on L. amazonensis and T. cruzi, than the referencedrugs. The activity was accompanied by significantly lower cytotoxicity on the murine macrophage cell line.Moreover, compounds 2, 3, 5-7, 9 and 10 showed more potent activity than the reference drug against theintracellular amastigotes forms of L. amazonensis and T.cruzi, with a good selectivity index on a mammalian cellline. In addition, withaferin A analogues 3, 5-7, 9 and 10 induce programmed cell death through a process ofapoptosis-like and autophagy. These results strengthen the anti-parasitic potential of withaferin A-related steroids against neglected tropical diseases caused by Leishmania spp. and T. cruzi parasites.
YR 2023
FD 2023
LK http://riull.ull.es/xmlui/handle/915/35887
UL http://riull.ull.es/xmlui/handle/915/35887
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 09-nov-2024