Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi.

Autor: Coelho GS; Chemistry Department, ICEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Andrade JS; Chemistry Department, ICEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Xavier VF; Immunopathology Laboratory, NUPEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Sales Junior PA; René Rachou Institute, FIOCRUZ, Belo Horizonte, MG, Brazil., Rodrigues de Araujo BC; Chemistry Department, ICEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Fonseca KDS; Immunopathology Laboratory, NUPEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Caetano MS; Chemistry Department, ICEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Murta SMF; René Rachou Institute, FIOCRUZ, Belo Horizonte, MG, Brazil., Vieira PM; Immunopathology Laboratory, NUPEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Carneiro CM; Immunopathology Laboratory, NUPEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil., Taylor JG; Chemistry Department, ICEB, Federal University of Ouro Preto, Ouro Preto, MG, Brazil.
Jazyk: angličtina
Zdroj: Chemical biology & drug design [Chem Biol Drug Des] 2019 Mar; Vol. 93 (3), pp. 337-350. Date of Electronic Publication: 2018 Nov 27.
DOI: 10.1111/cbdd.13420
Abstrakt: 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.
(© 2018 John Wiley & Sons A/S.)
Databáze: MEDLINE
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