Flipo, Marion; Desroses, Matthieu; Lecat-Guillet, Nathalie; Villemagne, Baptiste; Blondiaux, Nicolas; Leroux, Florence; Piveteau, Catherine; Mathys, Vanessa; Flament, Marie-Pierre; Siepmann, Juergen; Villeret, Vincent; Wohlkonig, Alexandre; Wintjens, Rene; Soror, Sameh H.; Christophe, Thierry; Jeon, Hee Kyoung; Locht, Camille; Brodin, Priscille; Deprez, Benoit; Baulard, Alain R.; Willand, Nicolas published the artcile< Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors>, Electric Literature of 1003-32-3, the main research area is oxadiazole EthR inhibitor preparation structure tuberculosis pharmacokinetics.
Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.
Journal of Medicinal Chemistry published new progress about Homo sapiens. 1003-32-3 belongs to class thiazole, and the molecular formula is C4H3NOS, Electric Literature of 1003-32-3.
Referemce:
Thiazole | C3H3NS – PubChem,
Thiazole | chemical compound | Britannica