期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 167, 期 -, 页码 426-438出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.023
关键词
Ethionamide; EthR2; Fragment-based drug design; Tropinone; Tuberculosis
资金
- l'Agence Nationale de la Recherche (ANR), France [ANR-14-CE14-0027-01]
- PRIM (NewBio4Tb)
- Societe d'Acceleration du Transfert de Technologie Nord
- Institut National de la Sante et de la Recherche Medicale, Universite de Lille, Institut Pasteur de Lille, Centre National de la Recherche Scientifique, Region Hauts-de-France [12000080]
- Region Hauts-de-France (France)
- Ministere de la Jeunesse, de l'Education Nationale et de la Recherche (MJENR)
- Fonds Europeens de Developpement Regional (FEDER)
- Lille University
Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis, represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis. Very recently, we identified that inhibition of a transcriptional repressor, termed EthR2, derepresses a new bioactivation pathway that results in the boosting of ethionamide activation. Herein, we describe the identification of potent EthR2 inhibitors using fragment-based screening and structure based optimization. A target-based screening of a fragment library using thermal shift assay followed by X-ray crystallography identified 5 hits. Rapid optimization of the tropinone chemical series led to compounds with improved in vitro potency. (C) 2019 Elsevier Masson SAS. All rights reserved.
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