RT info:eu-repo/semantics/article
T1 In Vitro Susceptibility of Kinetoplastids to Celastroloids from Maytenus chiapensis
A1 Núñez, Marvin J.
A1 Martínez, Morena L.
A1 López Arencibia, Atteneri
A1 Bethencourt Estrella, Carlos Javier
A1 San Nicolás Hernández, Desirée
A1 Jiménez Díaz, Ignacio Antonio
A1 Lorenzo Morales, Jacob
A1 Piñero Barroso, José Enrique
A1 López Bazzocchi, Isabel
K1 Chagas disease
K1 bioactive natural products
K1 leishmaniasis
AB Leishmaniasis and Chagas are among the most significant neglected tropicaldiseases. Due to several drawbacks with the current chemotherapy, developing new antikinetoplastiddrugs has become an urgent issue. In the present work, a bioassay-guidedinvestigation of the root bark of Maytenus chiapensis on Leishmania amazonensis andTrypanosoma cruzi led to the identification of two D:A-friedo-nor-oleanane triterpenoids(celastroloids), 20b-hydroxy-tingenone (celastroloid 5) and 3-O-methyl-6-oxo-tingenol(celastroloid 8), as promising antikinetoplastid leads. They displayed higher potency on L.amazonensis promastigotes (50% inhibitory concentrations [IC50s], 0.44 and 1.12mM,respectively), intracellular amastigotes (IC50s, 0.83 and 1.91mM, respectively), and T. cruziepimastigote stage (IC50s, 2.61 and 3.41mM, respectively) than reference drugs miltefosineand benznidazole. This potency was coupled with an excellent selectivity index on murinemacrophages. Mechanism of action studies, including mitochondrial membrane potential(Dc m) and ATP-level analysis, revealed that celastroloids could induce apoptotic celldeath in L. amazonensis triggered by the mitochondria. In addition, the structure-activityrelationship is discussed. These findings strongly underline the potential of celastroloidsas lead compounds to develop novel antikinetoplastid drugs.
YR 2021
FD 2021
LK http://riull.ull.es/xmlui/handle/915/35935
UL http://riull.ull.es/xmlui/handle/915/35935
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DS Repositorio institucional de la Universidad de La Laguna
RD 27-nov-2024