Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase
| العنوان: | Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase |
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| المؤلفون: | Talita Hortencio da Costa, Nubia Boechat, Edson Roberto da Silva, Juliana Custódio Bartholomeu, Mônica M. Bastos, Carolina C. P. Costa, Luiz C. S. Pinheiro |
| المصدر: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| بيانات النشر: | Wiley, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Pyrimidine, Mutant, Antiprotozoal Agents, Trypanothione, FARMACOLOGIA, Biochemistry, Cell Line, chemistry.chemical_compound, Drug Discovery, Humans, Enzyme Inhibitors, Leishmaniasis, Leishmania, Pharmacology, chemistry.chemical_classification, Arginase, biology, Organic Chemistry, Thiourea, biology.organism_classification, Pyrimidines, Enzyme, chemistry, Cell culture, Drug Design, Molecular Medicine, Polyamine |
| الوصف: | 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. |
| تدمد: | 1747-0277 |
| DOI: | 10.1111/cbdd.12566 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23e04c0bd6e6b0b5efaed1f32abda2f9 https://doi.org/10.1111/cbdd.12566 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....23e04c0bd6e6b0b5efaed1f32abda2f9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17470277 |
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| DOI: | 10.1111/cbdd.12566 |