Novel selective inhibitor of Leishmania (Leishmania) amazonensis arginase.
Chem Biol Drug Des
; 86(5): 969-78, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-25845502
Arginase is a glycosomal enzyme in Leishmania that is involved in polyamine and trypanothione biosynthesis. The central role of arginase in Leishmania (Leishmania) amazonensis was demonstrated by the generation of two mutants: one with an arginase lacking the glycosomal addressing signal and one in which the arginase-coding gene was knocked out. Both of these mutants exhibited decreased infectivity. Thus, arginase seems to be a potential drug target for Leishmania treatment. In an attempt to search for arginase inhibitors, 29 derivatives of the [1,2,4]triazolo[1,5-a]pyrimidine system were tested against Leishmania (Leishmania) amazonensis arginase in vitro. The [1,2,4]triazolo[1,5-a]pyrimidine scaffold containing R1 = CF3 exhibited greater activity against the arginase rather than when the substituent R1 = CH3 in the 2-position. The novel compound 2-(5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)hydrazinecarbothioamide (30) was the most potent, inhibiting arginase by a non-competitive mechanism, with the Ki and IC50 values for arginase inhibition estimated to be 17 ± 1 µm and 16.5 ± 0.5 µm, respectively. These results can guide the development of new drugs against leishmaniasis based on [1,2,4]triazolo[1,5-a]pyrimidine derivatives targeting the arginase enzyme.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Arginasa
/
Pirimidinas
/
Tiourea
/
Inhibidores Enzimáticos
/
Leishmania
Límite:
Humans
Idioma:
En
Revista:
Chem Biol Drug Des
Asunto de la revista:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Brasil
Pais de publicación:
Reino Unido