Université Lille Nord de France, F-59000 Lille, France.
J Med Chem. 2012 Jul 26;55(14):6391-402. doi: 10.1021/jm300377g. Epub 2012 Jul 17.
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.
在本文中，我们描述了使用新型全分枝杆菌表型测定法筛选 14640 种化合物库，以发现 EthR 的抑制剂，EthR 是一种转录阻遏物，与结核分枝杆菌对二线抗结核药物乙硫异烟胺的固有耐药性有关。从这次筛选中，发现了一个含有 N- 苯基苯氧基乙酰胺基序的新的 EthR 抑制剂化学家族。与 EthR 结晶的最有效化合物的 X 射线结构激发了针对 EthR 的 960 个成员的聚焦文库的合成。使用 EthR 上的快速热位移测定法在体外测试这些化合物，以加速优化。最好的化合物在更大的规模上进行合成，并在感染结核分枝杆菌的巨噬细胞中证实是有效的乙硫异烟胺增强剂。最后，最佳优化类似物与 EthR 的共结晶揭示了配体在结合口袋中的意外重新定向。
