Department of Pharmaceutical Engg. and Tech., IIT-Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
Department of Pharmacology and Toxicology, NIPER-Hyderabad, Hyderabad, 500037, India.
ACS Infect Dis. 2024 Oct 11;10(10):3699-3711. doi: 10.1021/acsinfecdis.4c00710. Epub 2024 Oct 3.
The nonproton pumping type II NADH dehydrogenase in is essential for meeting the energy needs in terms of ATP under normal aerobic and stressful hypoxic environmental states. Type II NADH dehydrogenase conduits electrons into the electron transport chain in , which results in ATP synthesis. Therefore, the inhibition of NDH-2 ensures the abolishment of the entire ATP synthesis machinery. Also, type II NADH dehydrogenase is absent in the mammalian genome, thus making it a potential target for antituberculosis drug discovery. Herein, we have screened a commercially available library of drug-like molecules and have identified a hit having a benzimidazole core moiety (, H37Rv mc6230; minimum inhibitory concentration (MIC) = 16 μg/mL and ATP IC = 0.23 μg/mL) interfering with the oxidative phosphorylation pathway. Extensive medicinal chemistry optimization resulted in analogue with MIC = 4 μg/mL and ATP IC = 0.05 μg/mL against the H37Rv mc6230 strain of . Compounds and were found to be active against mono- and multidrug-resistant mycobacterium strains and demonstrated a bactericidal response. The Peredox-mCherry experiment and identification of single-nucleotide polymorphisms in mutants of (a known type II NADH dehydrogenase inhibitor) were used to confirm the molecules as inhibitors of the type II NADH dehydrogenase enzyme. The safety index >10 for the test active molecules revealed the safety of test molecules.
非质子泵 II 型 NADH 脱氢酶在 中对于满足正常需氧和应激缺氧环境状态下的 ATP 能量需求至关重要。II 型 NADH 脱氢酶将电子导入 中的电子传递链，从而导致 ATP 合成。因此，NDH-2 的抑制可确保整个 ATP 合成机制的废除。此外，哺乳动物基因组中不存在 II 型 NADH 脱氢酶，因此它成为抗结核药物发现的潜在靶点。在此，我们筛选了商业上可用的药物样分子文库，并鉴定出一个具有苯并咪唑核心部分的命中物（，H37Rv mc6230；最小抑制浓度（MIC）= 16 μg/mL，ATP IC = 0.23 μg/mL），该命中物干扰氧化磷酸化途径。广泛的药物化学优化导致类似物 具有 MIC = 4 μg/mL 和 ATP IC = 0.05 μg/mL ，针对 H37Rv mc6230 株。化合物 和 被发现对单药和多药耐药分枝杆菌菌株具有活性，并表现出杀菌反应。Peredox-mCherry 实验和突变体中单核苷酸多态性的鉴定（已知的 II 型 NADH 脱氢酶抑制剂）用于确认这些分子是 II 型 NADH 脱氢酶酶的抑制剂。测试活性分子的安全指数 >10 表明测试分子的安全性。
