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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Ligand efficiency driven design of new inhibitors of mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches
Journal of Medicinal Chemistry, Volume 57, No. 11, Year 2014
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Description
Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. As a way to identify new potent ligands of this protein, we have developed fragment-based approaches. In the current study, we combined surface plasmon resonance assay, X-ray crystallography, and ligand efficiency driven design for the rapid discovery and optimization of new chemotypes of EthR ligands starting from a fragment. The design, synthesis, and in vitro and ex vivo activities of these compounds will be discussed. © 2014 American Chemical Society.
Authors & Co-Authors
Villemagne, Baptiste
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Flipo, Marion
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Blondiaux, Nicolas
France, Lille
Université de Lille
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
France, Lille
Center for Infection and Immunity of Lille Ciil
Crauste, Céline
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Malaquin, Sandra
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Leroux, Florence
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Piveteau, Catherine
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Villeret, Vincent
France, Lille
Université de Lille
Belgium, Brussels
Université Libre de Bruxelles
Brodin, Priscille M.
France, Lille
Université de Lille
France, Lille
Institut Pasteur de Lille
France, Lille
Center for Infection and Immunity of Lille Ciil
Villoutreix, Bruno O.
France, Paris
Inserm
France, Paris
Université Paris Cité
Sperandio, Olivier
France, Paris
Inserm
France, Paris
Université Paris Cité
Soror, Sameh Hamdy
Belgium, Ghent
Vlaams Instituut Voor Biotechnologie
Egypt, Helwan
Faculty of Pharmacy
Wohlkönig, Alexandre
Belgium, Ghent
Vlaams Instituut Voor Biotechnologie
Wintjens, René T.
France, Lille
Université de Lille
Belgium, Brussels
Université Libre de Bruxelles
Déprez, Benoît P.
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Baulard, Alain R.
France, Lille
Université de Lille
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
France, Lille
Center for Infection and Immunity of Lille Ciil
Willand, Nicolas
France, Lille
Université de Lille
France, Paris
Inserm
France, Lille
Institut Pasteur de Lille
France, Lille
Prim
Statistics
Citations: 62
Authors: 17
Affiliations: 9
Identifiers
Doi:
10.1021/jm500422b
ISSN:
00222623
e-ISSN:
15204804