Abstract：
Through a comprehensive molecular docking study, a unique series of naphthoquinones clubbed azetidinone scaffolds was arrived with promising binding affinity to Mycobacterial Cytbc1 complex, a drug target chosen to kill multi-drug resistant Mycobacterium tuberculosis (MDR-Mtb). Five compounds from series-2, 2a, 2c, 2g, 2h, and 2j, showcased significant in vitro anti-tubercular activities against Mtb H37Rv and MDR clinical isolates. Further, synergistic studies of these compounds in combination with INH and RIF revealed a potent bactericidal effect of compound 2a at concentration of 0.39 μg/mL, and remaining (2c, 2g, 2h, and 2j) at 0.78 μg/mL. Exploration into the mechanism study through chemo-stress assay and proteome profiling uncovered the down-regulation of key proteins of electron-transport chain and Cytbc1 inhibition pathway. Metabolomics corroborated these proteome findings, and heightened further understanding of the underlying mechanism. Notably, in vitro and in vivo animal toxicity studies demonstrated minimal toxicity, thus underscoring the potential of these compounds as promising anti-TB agents in combination with RIF and INH. These active compounds adhered to Lipinski\'s Rule of Five, indicating the suitability of these compounds for drug development. Particular significance of molecules NQ02, 2a, and 2h, which have been patented (Published 202141033473).
摘要：
通过全面的分子对接研究,一系列独特的萘醌簇状氮杂环丁酮支架与分枝杆菌Cytbc1复合物具有良好的结合亲和力，选择杀死耐多药结核分枝杆菌（MDR-Mtb）的药物靶标。来自系列2、2a、2c,2g,2h,2j，显示了对MtbH37Rv和MDR临床分离株的显着体外抗结核活性。Further,这些化合物与异烟肼和RIF组合的协同研究表明，浓度为0.39μg/mL的化合物2a具有有效的杀菌作用。剩下的(2c，2g,2h,和2j)为0.78μg/mL。通过化学应激测定和蛋白质组谱分析对机制研究进行了探索，揭示了电子传递链和Cytbc1抑制途径的关键蛋白的下调。代谢组学证实了这些蛋白质组的发现，并加深了对潜在机制的进一步理解。值得注意的是,体外和体内动物毒性研究表明毒性最小，因此强调了这些化合物与RIF和INH联合作为有前途的抗结核药的潜力。这些活性化合物遵守Lipinski的“五”法则，表明这些化合物对药物开发的适用性。分子NQ02、2a、和2小时，已获得专利(已发布202141033473)。
