title: Novel selective inhibitor of Leishmania (Leishmania) amazonensis arginase.
abstract: 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.
authors.affiliation: Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, SP, 13635-900, Brazil.
authors.forename: Edson R
authors.initials: ER
authors.lastname: da Silva
authors.affiliation: Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ, Rio de Janeiro, RJ, 21041-250, Brazil.
authors.forename: Nubia
authors.initials: N
authors.lastname: Boechat
authors.affiliation: Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ, Rio de Janeiro, RJ, 21041-250, Brazil.
authors.forename: Luiz C S
authors.initials: LC
authors.lastname: Pinheiro
authors.affiliation: Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ, Rio de Janeiro, RJ, 21041-250, Brazil.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bastos
authors.affiliation: Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ, Rio de Janeiro, RJ, 21041-250, Brazil.
authors.forename: Carolina C P
authors.initials: CC
authors.lastname: Costa
authors.affiliation: Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, SP, 13635-900, Brazil.
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Bartholomeu
authors.affiliation: Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, SP, 13635-900, Brazil.
authors.forename: Talita H
authors.initials: TH
authors.lastname: da Costa
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007891:Leishmania / Q000187:drug effects / Q000201:enzymology*; D007896:Leishmaniasis / Q000188:drug therapy; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000609399:2-(5-methyl-2-(trifluoromethyl)-(1,2,4)triazolo(1,5-a)pyrimidin-7-yl)hydrazinecarbothioamide; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D001119:Arginase; D013890:Thiourea
keywords: Leishmania; arginase; polyamines; triazolopyrimidine; trifluoromethyl; trypanothione