Ligand Efficiency Driven Design of New Inhibitors of Mycobacterium tuberculosis Transcriptional Repressor EthR Using Fragment Growing, Merging, and Linking Approaches

• Published in: Journal of medicinal chemistry Vol. 57; no. 11; pp. 4876 - 4888
• Main Authors: Villemagne, Baptiste, Flipo, Marion, Blondiaux, Nicolas, Crauste, Céline, Malaquin, Sandra, Leroux, Florence, Piveteau, Catherine, Villeret, Vincent, Brodin, Priscille, Villoutreix, Bruno O, Sperandio, Olivier, Soror, Sameh H, Wohlkönig, Alexandre, Wintjens, René, Deprez, Benoit, Baulard, Alain R, Willand, Nicolas
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.06.2014; Amer Chemical Soc
• Subjects: Animals; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Cell Line; Chemistry, Medicinal; Crystallography, X-Ray; Life Sciences; Life Sciences & Biomedicine; Mice; Molecular Docking Simulation; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - metabolism; Pharmacology & Pharmacy; Protein Binding; Repressor Proteins - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; Surface Plasmon Resonance; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; CYP121; ACTIVATION; SERIES; ETHIONAMIDE BOOSTERS; DRUG DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500422b

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.