Discovery of Novel N-Phenylphenoxyacetamide Derivatives as EthR Inhibitors and Ethionamide Boosters by Combining High-Throughput Screening and Synthesis
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- 作者：Marion Flipo ; Nicolas Willand ; Nathalie Lecat-Guillet ; Candide Hounsou ; Matthieu Desroses ; Florence Leroux ; Zo茅 Lens ; Vincent Villeret ; Alexandre Wohlk枚nig ; Ren茅 Wintjens ; Thierry Christophe ; Hee Kyoung Jeon ; Camille Locht ; Priscille Brodin ; Alain R Baulard ; Benoit D茅prez
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：July 26, 2012
- 年：2012
- 卷：55
- 期：14
- 页码：6391-6402
- 全文大小：642K
- 年卷期：v.55,no.14(July 26, 2012)
- ISSN：1520-4804
文摘
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.