Akester Jessica N, Njaria Paul, Nchinda Aloysius, Le Manach Claire, Myrick Alissa, Singh Vinayak, Lawrence Nina, Njoroge Mathew, Taylor Dale, Moosa Atica, Smith Anthony J, Brooks Elizabeth J, Lenaerts Anne J, Robertson Gregory T, Ioerger Thomas R, Mueller Rudolf, Chibale Kelly
Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
ACS Infect Dis. 2020 Jul 10;6(7):1951-1964. doi: 10.1021/acsinfecdis.0c00252. Epub 2020 Jun 15.
Phenotypic whole-cell screening against () in glycerol-alanine-salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone which was optimized for solubility by replacing the sulfone moiety with a sulfoxide . The synthesis and structure-activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound displayed favorable properties and was therefore selected for pharmacokinetic (PK) studies where it was found to be extensively metabolized to the sulfone . Both derivatives exhibited promising PK parameters; however, when was evaluated for efficacy in an acute TB infection mouse model, it was found to be inactive. In order to understand the and discrepancy, compound was subsequently retested using different strains cultured in different media. This revealed that activity was only observed in media containing glycerol and led to the hypothesis that glycerol was not used as a primary carbon source by in the mouse lungs, as has previously been observed. Support for this hypothesis was provided by spontaneous-resistant mutant generation and whole genome sequencing studies, which revealed mutations mapping to glycerol metabolizing genes indicating that the 2-aminoquinazolinones kill via a glycerol-dependent mechanism of action.
在补充了吐温80和铁的甘油 - 丙氨酸 - 盐（GASTE - Fe）培养基中针对（）进行表型全细胞筛选，鉴定出一种2 - 氨基喹唑啉酮命中化合物，砜，通过用亚砜取代砜部分对其溶解度进行了优化。合成及构效关系（SAR）研究确定了几种具有强效抗分枝杆菌活性的化合物，这些化合物代谢稳定且无细胞毒性。化合物表现出良好的（此处原文缺失相关内容）性质，因此被选用于药代动力学（PK）研究，结果发现它被广泛代谢为砜。两种衍生物均表现出有前景的PK参数；然而，当在急性结核病感染小鼠模型中评估其疗效时，发现它没有活性。为了理解这种（此处原文缺失相关内容）和差异，随后使用在不同培养基中培养的不同（此处原文缺失相关内容）菌株对化合物进行重新测试。结果表明，仅在含有甘油的培养基中观察到活性，并由此提出假设，即甘油在小鼠肺部未被（此处原文缺失相关内容）用作主要碳源，正如之前所观察到的那样。自发抗性突变体的产生和全基因组测序研究为这一假设提供了支持，这些研究揭示了映射到甘油代谢基因的突变，表明2 - 氨基喹唑啉酮通过依赖甘油的作用机制杀死（此处原文缺失相关内容）。
