Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

表型筛选了900种抗结核硝基咪唑衍生物的化合物库，这些化合物与昆虫前体有关，与原生动物寄生虫克鲁斯锥虫（查加斯病的病原体）有关，鉴定了几种结构多样的命中，其作用方式未知。初步分析后，体内首次概念验证进行了一项研究，其中每天一次口服7-取代的2-硝基咪唑并恶嗪类似物可将血液寄生虫病抑制到低水平或无法检测到的水平，尽管无法实现无菌治愈。有限的命中扩增研究以及针对内脏利什曼病的新化合物的反筛选为更好地评估最佳潜在药物奠定了基础，重点关注类药物的特性（溶解性，代谢稳定性和安全性）以及最大杀伤力在较短的时间内寄生虫。通过高度敏感的生物发光成像监测，在慢性感染小鼠模型中对一种优选的铅（58）进行的比较评估，为这种有前途的硝基咪唑并恶嗪类化合物提供了（部分）疗效的首个确凿证据。