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Synthesis, Structure-Activity Relationship, and Mechanistic Studies of Aminoquinazolinones Displaying Antimycobacterial Activity.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-05-29 , DOI: 10.1021/acsinfecdis.0c00252 Jessica N Akester 1 , Paul Njaria 2 , Aloysius Nchinda 1 , Claire Le Manach 1 , Alissa Myrick 1, 3 , Vinayak Singh 1, 3, 4 , Nina Lawrence 5 , Mathew Njoroge 5 , Dale Taylor 5 , Atica Moosa 6 , Anthony J Smith 7 , Elizabeth J Brooks 7 , Anne J Lenaerts 7 , Gregory T Robertson 7 , Thomas R Ioerger 8 , Rudolf Mueller 1 , Kelly Chibale 1, 2, 3, 4
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-05-29 , DOI: 10.1021/acsinfecdis.0c00252 Jessica N Akester 1 , Paul Njaria 2 , Aloysius Nchinda 1 , Claire Le Manach 1 , Alissa Myrick 1, 3 , Vinayak Singh 1, 3, 4 , Nina Lawrence 5 , Mathew Njoroge 5 , Dale Taylor 5 , Atica Moosa 6 , Anthony J Smith 7 , Elizabeth J Brooks 7 , Anne J Lenaerts 7 , Gregory T Robertson 7 , Thomas R Ioerger 8 , Rudolf Mueller 1 , Kelly Chibale 1, 2, 3, 4
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Phenotypic whole-cell screening against Mycobacterium tuberculosis (Mtb) in glycerol–alanine–salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone 1 which was optimized for solubility by replacing the sulfone moiety with a sulfoxide 2. The synthesis and structure–activity relationship (SAR) studies identified several compounds with potent antimycobacterial activity, which were metabolically stable and noncytotoxic. Compound 2 displayed favorable in vitro properties and was therefore selected for in vivo pharmacokinetic (PK) studies where it was found to be extensively metabolized to the sulfone 1. Both derivatives exhibited promising PK parameters; however, when 2 was evaluated for in vivo efficacy in an acute TB infection mouse model, it was found to be inactive. In order to understand the in vitro and in vivo discrepancy, compound 2 was subsequently retested in vitro using different Mtb 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 Mtb 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 Mtb in vitro via a glycerol-dependent mechanism of action.
中文翻译：
显示抗分枝杆菌活性的氨基喹唑啉酮的合成，结构-活性关系和机理研究。
表型全细胞筛选针对补充有吐温80和铁（GASTE-Fe）的甘油-丙氨酸-盐中的结核分枝杆菌（Mtb）导致鉴定出2-氨基喹唑啉酮命中化合物砜1，该化合物可通过替换来优化溶解度带有亚砜的砜部分2。合成和结构-活性关系（SAR）研究确定了几种具有有效抗分枝杆菌活性的化合物，它们在代谢上稳定且无细胞毒性。化合物2表现出良好的体外特性，因此被选择用于体内药代动力学（PK）研究，发现它被广泛代谢为砜1。两种衍生物均显示出有希望的PK参数。但是，当评估2在急性TB感染小鼠模型中的体内功效时，发现它没有活性。为了了解体外和体内差异，随后使用在不同培养基中培养的不同Mtb菌株在体外对化合物2进行了重新测试。这表明仅在含甘油的介质中观察到了活性，并导致了以下假设：甘油不被Mtb用作主要碳源。如先前所观察到的，在小鼠肺中的这种作用。自发抗性突变体的产生和全基因组测序研究提供了对这一假说的支持，该研究揭示了映射到甘油代谢基因的突变，表明2-氨基喹唑啉酮通过甘油依赖性的作用机制在体外杀死了Mtb。
更新日期：2020-07-10
中文翻译：
显示抗分枝杆菌活性的氨基喹唑啉酮的合成，结构-活性关系和机理研究。
表型全细胞筛选针对补充有吐温80和铁（GASTE-Fe）的甘油-丙氨酸-盐中的结核分枝杆菌（Mtb）导致鉴定出2-氨基喹唑啉酮命中化合物砜1，该化合物可通过替换来优化溶解度带有亚砜的砜部分2。合成和结构-活性关系（SAR）研究确定了几种具有有效抗分枝杆菌活性的化合物，它们在代谢上稳定且无细胞毒性。化合物2表现出良好的体外特性，因此被选择用于体内药代动力学（PK）研究，发现它被广泛代谢为砜1。两种衍生物均显示出有希望的PK参数。但是，当评估2在急性TB感染小鼠模型中的体内功效时，发现它没有活性。为了了解体外和体内差异，随后使用在不同培养基中培养的不同Mtb菌株在体外对化合物2进行了重新测试。这表明仅在含甘油的介质中观察到了活性，并导致了以下假设：甘油不被Mtb用作主要碳源。如先前所观察到的，在小鼠肺中的这种作用。自发抗性突变体的产生和全基因组测序研究提供了对这一假说的支持，该研究揭示了映射到甘油代谢基因的突变，表明2-氨基喹唑啉酮通过甘油依赖性的作用机制在体外杀死了Mtb。
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