Triclosan and isoniazid are known antitubercular compounds that have proven to be also active against Leishmania parasites. On these grounds, a collection of 37 diverse 1,2,3-triazoles based on the antitubercular molecules triclosan and 5-octyl-2-phenoxyphenol (8PP) were designed in search of novel structures with leishmanicidal activity and prepared using different alkynes and azides. The 37 compounds were assayed against Leishmania donovani, the etiological agent of leishmaniasis, yielding some analogs with activity at micromolar concentrations and against M. tuberculosis H37Rv resulting in scarce active compounds with an MIC of 20 μM. To study the mechanism of action of these catechols, we analyzed the inhibition activity of the library on the M. tuberculosis enoyl-ACP reductase (ENR) InhA, obtaining poor inhibition of the enzyme. The cytotoxicity against Vero cells was also tested, resulting in none of the compounds being cytotoxic at concentrations of up to 20 μM. Derivative 5f could be considered a valuable starting point for future antileishmanial drug development. The validation of a putative leishmanial InhA orthologue as a therapeutic target needs to be further investigated.

中文翻译：

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探索 1,2,3-三唑基三氯生类似物的化学空间以发现新的抗利什曼病化疗药物

三氯生和异烟肼是已知的抗结核化合物，已被证明对利什曼原虫也有活性。基于这些理由，设计了基于抗结核分子三氯生和 5-辛基-2-苯氧基苯酚 (8PP) 的 37 种不同的 1,2,3-三唑的集合，以寻找具有杀利什曼原虫活性的新型结构，并使用不同的炔烃和叠氮化物制备. 对 37 种化合物进行了针对多诺瓦利什曼原虫（利什曼病的病原体）的分析，产生了一些具有微摩尔浓度活性的类似物，并针对结核分枝杆菌H37Rv 产生了 MIC 为 20 μM 的稀有活性化合物。为了研究这些儿茶酚的作用机制，我们分析了文库对结核分枝杆菌烯酰-ACP 还原酶 (ENR) InhA，对该酶的抑制作用较差。还测试了对 Vero 细胞的细胞毒性，结果在高达 20 μM 的浓度下没有任何化合物具有细胞毒性。衍生物5f可被视为未来抗利什曼病药物开发的宝贵起点。需要进一步研究推定的利什曼原虫 InhA 直向同源物作为治疗靶点的验证。