Ethionamide Boosters: Synthesis, Biological Activity, and Structure鈭扐ctivity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors

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• 作者：Marion Flipo ; Matthieu Desroses ; Nathalie Lecat-Guillet ; Bertrand Dirie虂 ; Xavier Carette ; Florence Leroux ; Catherine Piveteau ; Fatma Demirkaya ; Zoe虂 Lens ; Prakash Rucktooa ; Vincent Villeret ; Thierry Christophe ; Hee Kyoung Jeon ; Camille Locht ; Priscille Brodin ; Benoit De虂prez ; Alain R. Baulard ; Nicolas Willand
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2994-3010
• 全文大小：1207K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

We report in this article an extensive structure鈭抋ctivity 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鈭扙thR 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.