• Marion Flipo, Matthieu Desroses, Nathalie Lecat-Guillet, Baptiste Villemagne, Nicolas Blondiaux, Florence Leroux, Catherine Piveteau, Vanessa Mathys, Marie-Pierre Flament, Juergen Siepmann, Vincent Villeret, Alexandre Wohlkönig, René Wintjens, Sameh H Soror, Thierry Christophe, Hee Kyoung Jeon, Camille Locht, Priscille Brodin, Benoit Déprez, Alain R Baulard, and Nicolas Willand.
• Université Lille Nord de France, F-59000 Lille, France.
• J. Med. Chem. 2012 Jan 12; 55 (1): 68-83.

AbstractMycobacterial 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.

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