1589818-98-3Relevant academic research and scientific papers
COMPOUNDS FOR USE IN THE TREATMENT OF MYCOBACTERIAL INFECTIONS
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, (2015/09/22)
The present invention concerns compounds of general formula (I): in which Y and Z are chosen from CH and N; T is chosen from CO or SO2; n is 1 to 3; R1 represents a group chosen, for example, from C1-C3 alkyl chains unsubstituted or substituted by fluorine, the unsubstituted or substituted cyclic, cyano, azido, alkoxy and phenyl groups; and R is chosen from the azido, cyano, alkinyl and 2-benzothiazolyl groups and an optionally substituted aromatic heterocycle with five vertices; and the use thereof in the treatment of bacterial and mycobacterial infections such as, for example, tuberculosis, leprosy and atypical mycobacterial infections. The present invention also concerns pharmaceutical compositions comprising, as the active ingredient, at least one of the abovementioned compounds and optionally an antibiotic activatable via the EthA pathway
Ligand efficiency driven design of new inhibitors of mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches
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.,Wohlk?nig, Alexandre,Wintjens, René,Deprez, Benoit,Baulard, Alain R.,Willand, Nicolas
, p. 4876 - 4888 (2014/07/07)
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.
