Martinez-Grau Maria Angeles, Valcarcel Isabel C Gonzalez, Early Julie V, Gessner Richard Klaus, de Melo Candice Soares, de la Nava Eva Maria Martin, Korkegian Aaron, Ovechkina Yulia, Flint Lindsay, Gravelle Anisa, Cramer Jeff W, Desai Prashant V, Street Leslie J, Odingo Joshua, Masquelin Thierry, Chibale Kelly, Parish Tanya
Lilly Research Laboratories, Eli Lilly and Company, Avda. de la Industria 30, 28108-Alcobendas, Madrid, Spain.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Bioorg Med Chem Lett. 2018 Jun 1;28(10):1758-1764. doi: 10.1016/j.bmcl.2018.04.028. Epub 2018 Apr 13.
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.
尽管近几十年来在寻找结核病新治疗方法方面加大了研究力度，但仍需要具有新作用机制的化合物。我们之前鉴定了一系列新型芳基恶二唑，它们对以丁酸盐为碳源的细菌具有抗结核活性。我们探索了该系列的构效关系。在所有结构域进行了结构修饰以提高效力和理化性质。许多化合物对利用丁酸盐而非葡萄糖作为碳源的结核分枝杆菌显示出亚微摩尔活性。这些化合物对真核细胞无细胞毒性或细胞毒性很低。三种化合物在小鼠药代动力学研究中进行了分析。血浆清除率低至中等，但口服暴露表明除首过代谢外，药物吸收还受溶解度限制。连接子中碱性氮的存在略微增加了溶解度，盐的形成优化了水溶性。我们的研究结果表明，1,3,4-恶二唑是有用的工具，值得进一步研究。
