Chagas disease has spread throughout the world mainly because of the migration of infected individuals. In Brazil, only benznidazole (Bnz) is used; however, it is toxic and not active in the chronic phase, and cases of resistance are described. This work aimed at the synthesis and the trypanocidal evaluation in vitro and in vivo of six new Bnz analogues (3–8). They were designed by exploring the bioisosteric substitution between the amide group contained in Bnz and the 1,2,3‐triazole ring. All the compounds were synthesized in good yields. With the exception of compound 7, the in vitro biological evaluation shows that all Bnz analogues were active against the amastigote form, whereas only compounds 3, 4, 5, and 8 were active against trypomastigote. Compounds 4 and 5 showed the most promising activities in vitro against the form of trypomastigote, being more active than Bnz. In vivo evaluation of compounds, 3–8 showed lower potency and higher toxicity than Bnz. Although the 1,2,3‐triazole ring has been described in the literature as an amide bioisostere, its substitution here has reduced the activity of the compounds and made them more toxic. Thus, further molecular optimization could provide novel therapeutic agents for Chagas’ disease.

中文翻译：

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苯并硝唑的新的基于1,2,3-三唑的类似物可用于克氏锥虫感染：体内和体外评估

恰加斯病已在世界范围内蔓延，这主要是由于受感染个体的迁徙。在巴西，仅使用苯并硝唑（Bnz）。但是，它有毒，在慢性期没有活性，并描述了耐药情况。这项工作的目的是在体内和体外合成六种新的Bnz类似物（3-8）并进行锥虫杀伤评估。他们是通过探索Bnz中的酰胺基团与1,2,3-三唑环之间的生物等位取代而设计的。所有化合物均以高收率合成。所用化合物的例外7，体外生物学评价表明，所有BNZ类似物人反对无鞭毛体形式的活性，而仅化合物3，4，5，还有8个对锥虫病有积极作用。化合物4和5在体外表现出最有前途的对抗锥虫病形式的活性，比Bnz具有更高的活性。体内评估化合物3-8比Bnz具有更低的效力和更高的毒性。尽管1,2,3-三唑环在文献中被描述为酰胺生物等排体，但此处被取代已降低了化合物的活性并使其更具毒性。因此，进一步的分子优化可以为查加斯病提供新的治疗剂。