da Silva Edson R, Boechat Nubia, Pinheiro Luiz C S, Bastos Monica M, Costa Carolina C P, Bartholomeu Juliana C, da Costa Talita H
Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, SP, 13635-900, Brazil.
Departamento de Síntese de Fármacos, Instituto de Tecnologia em Fármacos, Farmanguinhos - FIOCRUZ, Rio de Janeiro, RJ, 21041-250, Brazil.
Chem Biol Drug Des. 2015 Nov;86(5):969-78. doi: 10.1111/cbdd.12566. Epub 2015 May 14.
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.
精氨酸酶是利什曼原虫中的一种糖体酶，参与多胺和锥虫硫醇的生物合成。通过产生两种突变体证明了精氨酸酶在亚马逊利什曼原虫（Leishmania amazonensis）中的核心作用：一种突变体的精氨酸酶缺乏糖体定位信号，另一种突变体的精氨酸酶编码基因被敲除。这两种突变体的感染性均降低。因此，精氨酸酶似乎是治疗利什曼原虫病的潜在药物靶点。为了寻找精氨酸酶抑制剂，对29种[1,2,4]三唑并[1,5-a]嘧啶系统的衍生物进行了体外抗亚马逊利什曼原虫（Leishmania amazonensis）精氨酸酶的测试。含有R1 = CF3的[1,2,4]三唑并[1,5-a]嘧啶支架对精氨酸酶的活性高于2位取代基R1 = CH3时的活性。新型化合物2-(5-甲基-2-(三氟甲基)-[1,2,4]三唑并[1,5-a]嘧啶-7-基)肼基甲硫酰胺（30）活性最强，通过非竞争性机制抑制精氨酸酶，精氨酸酶抑制的Ki和IC50值估计分别为17±1μm和16.5±0.5μm。这些结果可为基于靶向精氨酸酶的[1,2,4]三唑并[1,5-a]嘧啶衍生物开发抗利什曼病新药提供指导。
