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Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis.

par Flipo, Marion;Willand, Nicolas;Lecat-Guillet, Nathalie;Hounsou, Candide;Desroses, Matthieu;Leroux, Florence;Lens, Zoé ;Villeret, Vincent ;Wohlkonig, Alexandre ;Wintjens, René ;Christophe, Thierry;Kyoung Jeon, Hee;Locht, Camille ;Brodin, Priscille;Baulard, Alain;Déprez, Benoit
Référence Journal of medicinal chemistry, 55, 14, page (6391-6402)
Publication Publié, 2012-07

Article révisé par les pairs

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Résumé :

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.