Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis.
J Med Chem
; 55(14): 6391-402, 2012 Jul 26.
Article
em En
| MEDLINE
| ID: mdl-22738293
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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Etionamida
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Descoberta de Drogas
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Ensaios de Triagem em Larga Escala
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Acetamidas
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Antituberculosos
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article