Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Bioorg Chem. 2022 Nov;128:105929. doi: 10.1016/j.bioorg.2022.105929. Epub 2022 Jun 7.
Twenty-three new riminophenazine and pyrido[3,2-b]quinoxaline derivatives were prepared and examined for their antimycobacterial activities against Mycobacterium marinum and Mycobacterium tuberculosis H37Rv, taking clofazimine (1) as the lead. Structure-activity relationship (SAR) analysis revealed that the introduction of a heterocycle or diethylamine substituted benzene moiety on the N-5 atom might be beneficial for activity. The most potent compound 7m also displayed enhanced activity against wild-type as well as multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB clinical isolates, with the MICs ranging from 0.08 to 1.25 μg/mL, especially effective toward strain M20A507, resistant to 1. Further mechanism study indicated that its anti-TB activity was independent of cell membrane disruption, but related to NDH-2 reduction and the resulting high ROS production. Our study provides instructive guidance for the further development of clofazimine derivatives into promising antimicrobial agents against MDR and XDR TB.
合成了 23 种新型利福平并吡啶[3,2-b]喹喔啉衍生物，并对其抗分枝杆菌活性进行了研究，以氯法齐明（1）为先导化合物。构效关系（SAR）分析表明，在 N-5 原子上引入杂环或二乙胺取代的苯环部分可能有利于活性。最有效的化合物 7m 对野生型以及耐多药（MDR）和广泛耐药（XDR）结核临床分离株也表现出增强的活性，MIC 范围为 0.08 至 1.25μg/mL，特别是对 M20A507 菌株有效，该菌株对 1 耐药。进一步的机制研究表明，其抗结核活性不依赖于细胞膜破坏，而是与 NDH-2 还原和由此产生的高 ROS 产生有关。我们的研究为进一步将氯法齐明衍生物开发成有前途的抗 MDR 和 XDR TB 的抗菌药物提供了指导。
