4DW6

Novel N-phenyl-phenoxyacetamide derivatives as potential EthR inhibitors and ethionamide boosters. Discovery and optimization using High-Throughput Synthesis.

Summary for 4DW6

• Entry DOI: 10.2210/pdb4dw6/pdb
• Descriptor: HTH-type transcriptional regulator EthR, N-[4-(1,3-benzothiazol-2-yl)phenyl]-2-(3-methoxyphenoxy)acetamide, AMMONIUM ION, ... (5 entities in total)
• Functional Keywords: tetr-family, transcritptional regulatory repressor, inhibitor, dna binding protein, transcription repressor-inhibitor complex, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 26637.85

Authors

Flipo, M.,Willand, N.,Lecat-Guillet, N.,Hounsou, C.,Desroses, M.,Leroux, F.,Lens, Z.,Villeret, V.,Wohlkonig, A.,Wintjens, R.,Christophe, T.,Jeon, H.K.,Locht, C.,Brodin, P.,Baulard, A.R.,Deprez, B. (deposition date: 2012-02-24, release date: 2013-03-27, Last modification date: 2024-02-28)

Primary citation

Flipo, M.,Willand, N.,Lecat-Guillet, N.,Hounsou, C.,Desroses, M.,Leroux, F.,Lens, Z.,Villeret, V.,Wohlkonig, A.,Wintjens, R.,Christophe, T.,Kyoung Jeon, H.,Locht, C.,Brodin, P.,Baulard, A.R.,Deprez, B.
Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis.
J.Med.Chem., 55:6391-6402, 2012

PubMed Abstract: 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.

PubMed: 22738293
DOI: 10.1021/jm300377g

Experimental method

X-RAY DIFFRACTION (2 Å)