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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

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Author(s):
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]
Total Authors: 7
Affiliation:
[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
Total Affiliations: 2
Document type: Journal article
Source: CHEMICAL BIOLOGY & DRUG DESIGN; v. 86, n. 5, p. 969-978, NOV 2015.
Web of Science Citations: 21
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 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)

FAPESP's process: 14/18642-1 - Arginase enzyme as a target to development of new prototype compound against Leishmania
Grantee:Edson Roberto da Silva
Support Opportunities: Regular Research Grants