Desai N C, Somani Hardik, Trivedi Amit, Bhatt Kandarp, Nawale Laxman, Khedkar Vijay M, Jha Prakash C, Sarkar Dhiman
Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002, Gujarat, India.
Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002, Gujarat, India.
Bioorg Med Chem Lett. 2016 Apr 1;26(7):1776-83. doi: 10.1016/j.bmcl.2016.02.043. Epub 2016 Feb 16.
A series of indole and pyridine based 1,3,4-oxadiazole derivatives 5a-t were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG both in active and dormant state. Compounds 5b, 5e, 5g and 5q exhibited very good antitubercular activity. All the newly synthesized compounds 5a-t were further evaluated for anti-proliferative activity against HeLa, A549 and PANC-1 cell lines using modified MTT assay and found to be noncytotoxic. On the basis of cytotoxicity and MIC values against Mycobacterium bovis BCG, selectivity index (SI) of most active compounds 5b, 5e, 5g and 5q was calculated (SI=GI50/MIC) in active and dormant state. Compounds 5b, 5e and 5g demonstrated SI values ⩾10 against all three cell lines and were found to safe for advance screening. Compounds 5a-t were further screened for their antibacterial activity against four bacteria strains to assess their selectivity towards MTB. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of enoyl reductase (InhA), which in turn helped to establish a structural basis of inhibition of mycobacteria. The potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for further optimization.
合成了一系列基于吲哚和吡啶的1,3,4-恶二唑衍生物5a - t，并评估了它们对结核分枝杆菌H37Ra（MTB）和牛分枝杆菌卡介苗（Mycobacterium bovis BCG）在活跃和休眠状态下的体外抗结核活性。化合物5b、5e、5g和5q表现出非常好的抗结核活性。使用改良的MTT法对所有新合成的化合物5a - t针对HeLa、A549和PANC - 1细胞系的抗增殖活性进行了进一步评估，发现它们无细胞毒性。根据对牛分枝杆菌卡介苗的细胞毒性和MIC值，计算了最具活性的化合物5b、5e、5g和5q在活跃和休眠状态下的选择性指数（SI = GI50/MIC）。化合物5b、5e和5g对所有三种细胞系的SI值均≥10，并且被发现对进一步筛选是安全的。对化合物5a - t针对四种细菌菌株的抗菌活性进行了进一步筛选，以评估它们对MTB的选择性。此外，分子对接研究揭示了这些化合物在烯酰还原酶（InhA）活性位点的结合模式，这反过来有助于建立抑制分枝杆菌的结构基础。这些化合物的效力、低细胞毒性和选择性使其成为进一步优化的有效先导化合物。
