Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Eur J Med Chem. 2020 Dec 1;207:112849. doi: 10.1016/j.ejmech.2020.112849. Epub 2020 Sep 18.
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.
对与丙型肝炎相关的 900 种抗结核硝基咪唑衍生物化合物库进行表型筛选，发现了几种结构不同的化合物，其作用机制未知。在初步分析后，进行了首次体内概念验证研究，其中每日口服一次的 7-取代 2-硝基咪唑噁嗪类似物可将血液寄生虫血症抑制到低水平或无法检测到的水平，尽管未能实现无菌治愈。有限的命中扩展研究以及针对内脏利什曼病的新化合物的反筛选为更深入地评估最佳先导化合物奠定了基础，重点是药物样特性（溶解度、代谢稳定性和安全性）和在更短的时间内最大程度地杀死寄生虫。在慢性感染小鼠模型中，通过高灵敏度生物发光成像监测一种优选先导化合物（58）的比较评估，首次提供了该有前途的硝基咪唑噁嗪类药物具有（部分）治愈功效的明确证据。
