Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

• DOI: 10.1111/cbdd.12566
• Publication Date: 2015-04-01T18:46:55Z
• Authors: Edson R. da Silva; Nubia Boechat; Luiz C. S. Pinheiro; Monica M. Bastos; Carolina C. P. Costa; Juliana C. Bartho...; Talita H. da Costa
• Keywords: Leishmania; 0303 health sciences; Arginase; Antiprotozoal Agents; Thiourea; Cell Line; 3. Good health; 03 medical and health sciences; Pyrimidines; Drug Design; Humans; Enzyme Inhibitors; Leishmaniasis

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.