Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

Autor(es)

da Silva, Edson R. ^[1] ; Boechat, Nubia ^[2] ; Pinheiro, Luiz C. S. ^[2] ; Bastos, Monica M. ^[2] ; Costa, Carolina C. P. ^[2] ; Bartholomeu, Juliana C. ^[1] ; da Costa, Talita H. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Vet Med, Fac Zootecnia & Engn Alimentos, BR-13635900 Pirassununga, SP - Brazil

^[2] Farmanguinhos FIOCRUZ, Inst Tecnol Farmacos, Dept Sintese Farmacos, BR-21041250 Rio De Janeiro, RJ - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 86, n. 5, p. 969-978, NOV 2015.
• Citações Web of Science: 21

Resumo

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 R-1 = CF3 exhibited greater activity against the arginase rather than when the substituent R-1 = 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 mu M and 16.5 +/- 0.5 mu M, 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. (AU)

• Processo FAPESP: 14/18642-1 - Utilização da enzima arginase como alvo terapêutico para desenvolvimento de protótipos leishmanicidas
• Beneficiário: Edson Roberto da Silva
• Modalidade de apoio: Auxílio à Pesquisa - Regular