التفاصيل البيبلوغرافية
العنوان:
Discovery of novel N-phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
المؤلفون:
Vincent Villeret , Priscille Brodin , Alexandre Wohlkonig , Marion Flipo , Florence Leroux , Alain R. Baulard , Camille Locht , Matthieu Desroses , Candide Hounsou , Nicolas Willand , Zoé Lens , Benoit Deprez , Nathalie Lecat-Guillet , René Wintjens , Thierry Christophe , Hee Kyoung Jeon
المساهمون:
Department of Bio-engineering Sciences, Structural Biology Brussels
المصدر:
Journal of medicinal chemistry . 55(14)
سنة النشر:
2012
مصطلحات موضوعية:
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
الوصف:
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.
تدمد:
1520-4804
الوصول الحر:
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a25de28772e1b3bc2a9e8abf586f0defTest https://pubmed.ncbi.nlm.nih.gov/22738293Test
حقوق:
RESTRICTED
رقم الانضمام:
edsair.doi.dedup.....a25de28772e1b3bc2a9e8abf586f0def
قاعدة البيانات:
OpenAIRE
