Title:Evaluation of the Novel Antichagasic Activity of [1,2,3]Triazolo[1,5-a]pyridine Derivatives
Volume: 17
Issue: 4
Author(s): Michel Lapier, Maria C. Zuniga-Lopez, Benjamin Aguilera-Venegas, Rosa Adam, Belen Abarca, Rafael Ballesteros, Rodrigo Lopez-Munoz, Juan Diego Maya and Claudio Olea-Azar
Affiliation:
Keywords:
Triazole/Pyridine derivatives, Trypanosoma cruzi, Reactive oxygen species, CYP51, Sterol pathways, Mass spectrometry.
Abstract: Background: Trypanosoma cruzi is the causative agent of Chagas disease. This parasite is
vulnerable to the effects of ROS as its main defense mechanism against exogenous agents trypanothione
is also another weakness of the parasite that investigated related to the inhibition of enzymes
belonging P450 system, mainly CYP51. In our group we have synthesized a series of triazoles known
as [1,2,3]triazolo[1,5-a]pyridyl ketones, and pyridyl ketones. These families have shown interesting
structural features due to the presence of electron withdrawing moieties attached to the main heterocycle
(triazoles and/or pyridines) and are proposed as potential target in the parasite, by the presence of
the carbonyl group being able to be reduced and form a free radical that could interact with molecular
oxygen generating ROS in the parasite. Furthermore, the triazole ring and pyridines have been considered
as potent inhibitors of sterol biosynthesis, the lock being part CYP51.
Result: Our results showed that the series is capable of generating a stable radical species and generate
ROS in the parasite. On the other hand these molecules are potent inhibitors of enzymes belonging to
the complex P450. We have focused on the inhibition of ergosterol biosynthesis demonstrating that triazole/
pyridine families are able to affect this pathway being observed the accumulation of squalene and
lanosterol.
