Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi.
No Thumbnail Available
Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi
and affects about 8 million people in 21 countries in Latin America. The main form
of treatment of this disease is still based on the use of two drugs, benznidazole and
nifurtimox, which both present low cure rates in the chronic phase and often have
serious side-effects. Herein, we describe the synthesis of tricyclic coumarins that
were obtained via NHC organocatalysis and evaluation of their trypanocidal activity.
Molecular docking studies against trypanosomal enzyme triosephosphate isomerase
(TIM) were carried out, as well as a theoretical study of the physicochemical parameters.
The tricyclic coumarins were tested in vitro against the intracellular forms of
Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the
reference drug benznidazole. The trypanocidal activity of the lead compound was
rationalized by molecular docking study which suggested the strong interaction with
the enzyme TIM by T. cruzi and therefore indicating a possible mode of action.
Furthermore, the selectivity index of eight tricyclic coumarins with high anti-T. cruzi
activity was above 50 and thus showing that these lead compounds are viable candidates
for further in vivo assays.
Description
Keywords
Chagas disease, In silico, Isocoumarins, Organocatalysis, Triosephosphate isomerase
Citation
COELHO, G. S. et al. Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi. Chemical Biology & Drug Design, v. 93, p. 337-335, mar. 2019. Disponível em: <https://onlinelibrary.wiley.com/doi/full/10.1111/cbdd.13420>. Acesso em: 21 fev. 2019.