Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas’ disease.

中文翻译：

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5-氨基-1,2,3-三唑-4-甲酰胺系列抗克氏锥虫的发现和优化

由原生动物寄生虫克氏锥虫引起的恰加斯病，是拉丁美洲流行地区心脏相关死亡的最常见原因。迫切需要新的更安全的治疗方法，因为目前的标准治疗选择苯硝唑和硝呋莫司具有显着的副作用，并且仅在感染的急性期有效，而在慢性期的疗效有限。针对受感染的 VERO 细胞中的细胞内寄生虫的表型高含量筛选用于鉴定 5-氨基-1,2,3-三唑-4-甲酰胺 (ATC) 的新型命中系列。ATC 系列的优化提高了效力、水溶性和代谢稳定性，这结合起来显着改善了口服暴露。减轻潜在的 Ames 和 hERG 责任最终导致了两种有前途的化合物，