• Marion Flipo, Matthieu Desroses, Nathalie Lecat-Guillet, Bertrand Dirié, Xavier Carette, Florence Leroux, Catherine Piveteau, Fatma Demirkaya, Zoé Lens, Prakash Rucktooa, Vincent Villeret, Thierry Christophe, Hee Kyoung Jeon, Camille Locht, Priscille Brodin, Benoit Déprez, Alain R Baulard, and Nicolas Willand.
• Université Lille Nord de France, Lille, France.
• J. Med. Chem. 2011 Apr 28; 54 (8): 2994-3010.

AbstractWe report in this article an extensive structure-activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were consistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.

32 keywords...

hide…