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Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
- Source :
- Journal of medicinal chemistry. 55(14)
- Publication Year :
- 2012
-
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. © 2012 American Chemical Society.
- Subjects :
- Models, Molecular
Thermal shift assay
Protein Conformation
High-throughput screening
Binding pocket
Antitubercular Agents
Computational biology
Chemistry Techniques, Synthetic
Ligands
Cell Line
Mycobacterium tuberculosis
Mice
Acetamides
Drug Discovery
medicine
Animals
Ethionamide
Antituberculosis drug
biology
Phenotypic assay
Chemistry
Macrophages
Drug Synergism
biology.organism_classification
Combinatorial chemistry
High-Throughput Screening Assays
Repressor Proteins
Transcriptional Repressor
Molecular Medicine
medicine.drug
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 55
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....a25de28772e1b3bc2a9e8abf586f0def