Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University, Alexandria 21311, Egypt.
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria 21321, Egypt.
Int J Mol Sci. 2022 Apr 24;23(9):4706. doi: 10.3390/ijms23094706.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is still a serious public health concern around the world. More treatment strategies or more specific molecular targets have been sought by researchers. One of the most important targets is M. tuberculosis' enoyl-acyl carrier protein reductase InhA which is considered a promising, well-studied target for anti-tuberculosis medication development. Our team has made it a goal to find new lead structures that could be useful in the creation of new antitubercular drugs. In this study, a new class of 1,2,3- and 1,2,4-triazole hybrid compounds was prepared. Click synthesis was used to afford 1,2,3-triazoles scaffold linked to 1,2,4-triazole by fixable mercaptomethylene linker. The new prepared compounds have been characterized by different spectroscopic tools. The designed compounds were tested in vitro against the InhA enzyme. At 10 nM, the inhibitors and successfully and totally (100%) inhibited the InhA enzyme. The IC values were calculated using different concentrations. With IC values of 0.074 and 0.13 nM, 7c and 7e were the most promising InhA inhibitors. Furthermore, a molecular docking investigation was carried out to support antitubercular activity as well as to analyze the binding manner of the screened compounds with the target InhA enzyme's binding site.
结核分枝杆菌引起的结核病仍然是全世界严重的公共卫生问题。研究人员一直在寻找更多的治疗策略或更具体的分子靶点。其中最重要的靶点之一是结核分枝杆菌的烯酰基载体蛋白还原酶 InhA，它被认为是抗结核药物开发的一个有前途、研究充分的靶点。我们的团队一直致力于寻找新的先导结构，这些结构可能有助于开发新的抗结核药物。在这项研究中，合成了一类新的 1,2,3-和 1,2,4-三唑杂合化合物。点击合成用于通过固定的巯基亚甲基接头将 1,2,3-三唑支架连接到 1,2,4-三唑上。新制备的化合物通过不同的光谱工具进行了表征。设计的化合物在体外针对 InhA 酶进行了测试。在 10 nM 时，抑制剂 和 成功且完全（100%）抑制了 InhA 酶。使用不同浓度计算了 IC 值。化合物 7c 和 7e 的 IC 值分别为 0.074 和 0.13 nM，是最有前途的 InhA 抑制剂。此外，还进行了分子对接研究，以支持抗结核活性，并分析筛选化合物与靶标 InhA 酶结合位点的结合方式。
