Li Yu-Li, Zhang Chun-Lin, Zhang Dong-Feng, Lu Yu, Wang Bin, Zheng Mei-Qin, Li Chun, Yin Da-Li, Huang Hai-Hong
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Yao Xue Xue Bao. 2012 Jun;47(6):745-54.
A series of novel riminophenazine derivatives bearing an alkyl substituent attached to N-5 and imino nitrogen at C-3 position of the phenazine ring were obtained through rational drug design, aiming to maintain high anti-tubercular activity, lower toxicity and reduce lipophilicity. All target compounds were prepared by utilizing simple and flexible synthetic route and evaluated against Mycobacterium tuberculosis H37Rv and screened for mammalian cytotoxicity. The results demonstrated that compounds with a cyclopropyl substituent at N-5 position were more active than the reference compound clofazimine. In particular, 2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl) imino-3, 5-dihydrophenazine (25) was found to be the most potent compound with low cytotoxicity and lipophilicity. This compound could serve as a valuable lead molecule for further optimization.
通过合理的药物设计，获得了一系列新型的利福喷丁衍生物，这些衍生物在吩嗪环的N-5位带有烷基取代基，在C-3位带有亚氨基氮，旨在保持高抗结核活性、降低毒性并减少亲脂性。所有目标化合物均通过简单灵活的合成路线制备，并针对结核分枝杆菌H37Rv进行了评估，并筛选了其对哺乳动物的细胞毒性。结果表明，N-5位带有环丙基取代基的化合物比参考化合物氯法齐明更具活性。特别是，2-(4-氯苯胺基)-5-环丙基-3-(4-甲氧基环己基)亚氨基-3,5-二氢吩嗪(25)被发现是最有效的化合物，具有低细胞毒性和亲脂性。该化合物可作为进一步优化的有价值的先导分子。
