新型烷基取代的亚胺吩嗪类化合物的合成和抗结核活性研究(英文)  

Synthesis and anti-tubercular activity of novel alkyl substituted riminophenazine derivatives

作　　者：李玉立 张春林 张东峰 陆宇[2] 王彬[2] 郑梅琴[2] 李春[1] 尹大力 黄海洪 

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,活性物质发现与适药化北京市重点实验室,北京100050 [2]北京市结核病胸部肿瘤研究所,首都医科大学附属北京胸科医院,北京101149

出　　处：《药学学报》2012年第6期745-754,共10页Acta Pharmaceutica Sinica

基　　金：Project supported by National Science and Technology Project of China(2009ZX09102-054);the Global Alliance for TB Drug Development financial support of this project

摘　　要：通过合理药物设计,合成了一系列在亚胺吩嗪环的N-5位和C-3位的亚胺基上同时引入烷基取代的衍生物,目的在于获得高活性、低毒性及亲脂性降低的新型亚胺吩嗪类抗结核药物。采用简便方法合成了19个目标化合物,并进行了抗结核分支杆菌H37Rv活性测试和细胞毒性考察。研究结果发现,在N-5位上具有环丙基取代的化合物较先导物氯苯吩嗪具有更强的抗结核活性,尤其是化合物25,不仅活性明显提高,且具有较低的细胞毒性和脂溶性,为进一步的结构优化提供了重要参考,值得深入研究。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.

关 键 词：亚胺吩嗪 抗结核活性 氯苯吩嗪 烷基取代基 亲脂性 

分 类 号：R916[医药卫生—药学]