Open AccessIn Vitro Susceptibility of Kinetoplastids to Celastroloids from Maytenus chiapensis
Author(s) -
Marvin J. Núñez,
Morena L. Martínez,
Atteneri López-Arencibia,
Carlos J. Bethencourt-Estrella,
Desirée San Nicolás-Hernández,
Ignacio A. Jiménez,
Jacob LorenzoMorales,
Isabel L. Bazzocchi
Publication year - 2021
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.02236-20
Subject(s) - benznidazole , amastigote , trypanosoma cruzi , miltefosine , biology , leishmania , leishmania mexicana , pharmacology , in vitro , antiparasitic , chagas disease , potency , leishmaniasis , microbiology and biotechnology , biochemistry , virology , immunology , parasite hosting , visceral leishmaniasis , medicine , pathology , world wide web , computer science
Leishmaniasis and Chagas are among the most significant neglected tropical diseases. Due to several drawbacks with the current chemotherapy, developing new antikinetoplastid drugs has become an urgent issue. In the present work, a bioassay-guided investigation of the root bark of Maytenus chiapensis on Leishmania amazonensis and Trypanosoma cruzi led to the identification of two D:A -friedo-nor-oleanane triterpenoids (celastroloids), 20β-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 [IC 50 s], 0.44 and 1.12 μM, respectively), intracellular amastigotes (IC 50 s, 0.83 and 1.91 μM, respectively), and T. cruzi epimastigote stage (IC 50 s, 2.61 and 3.41 μM, respectively) than reference drugs miltefosine and benznidazole. This potency was coupled with an excellent selectivity index on murine macrophages. Mechanism of action studies, including mitochondrial membrane potential (Δψm) and ATP-level analysis, revealed that celastroloids could induce apoptotic cell death in L. amazonensis triggered by the mitochondria. In addition, the structure-activity relationship is discussed. These findings strongly underline the potential of celastroloids as lead compounds to develop novel antikinetoplastid drugs.