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Synthesis and biological evaluation of aryl-oxadiazoles as inhibitors of Mycobacterium tuberculosis. 2018
Maria Angeles Martinez-Grau, and
Isabel C Gonzalez Valcarcel, and
Julie V Early, and
Richard Klaus Gessner, and
Candice Soares de Melo, and
Eva Maria Martin de la Nava, and
Aaron Korkegian, and
Yulia Ovechkina, and
Lindsay Flint, and
Anisa Gravelle, and
Jeff W Cramer, and
Prashant V Desai, and
Leslie J Street, and
Joshua Odingo, and
Thierry Masquelin, and
Kelly Chibale, and
Tanya Parish
Lilly Research Laboratories, Eli Lilly and Company, Avda. de la Industria 30, 28108-Alcobendas, Madrid, Spain.
Despite increased research efforts to find new treatments for tuberculosis in recent decades, compounds with novel mechanisms of action are still required. We previously identified a series of novel aryl-oxadiazoles with anti-tubercular activity specific for bacteria using butyrate as a carbon source. We explored the structure activity relationship of this series. Structural modifications were performed in all domains to improve potency and physico-chemical properties. A number of compounds displayed sub-micromolar activity against M. tuberculosis utilizing butyrate, but not glucose as the carbon source. Compounds showed no or low cytotoxicity against eukaryotic cells. Three compounds were profiled in mouse pharmacokinetic studies. Plasma clearance was low to moderate but oral exposure suggested solubility-limited drug absorption in addition to first pass metabolism. The presence of a basic nitrogen in the linker slightly increased solubility, and salt formation optimized aqueous solubility. Our findings suggest that the 1,3,4-oxadiazoles are useful tools and warrant further investigation.
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