期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 14, 页码 6391-6402出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm300377g
关键词
-
资金
- Institut Pasteur Korea [K204EA000001-08E0100-00100, K204EA000001-09E0100-00100]
- Universite de Lille Nord de France
- Institut Pasteur de Lille
- CNRS
- European Union
- Region Nord-Pas de Calais
- Fonds europeen de developpement regional (FEDER) [09220019, 09220020 PRESAGE 31510]
- Agence Nationale de la Recherche (ANR) [ANR-06-EMPB-033]
- PRIM [11002859]
- Research Associate at the Belgian Fund for Scientific Research (FNRS)
In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据