新型苯并咪唑衍生物的设计、合成和抗结核活性研究(英文)  

Design and synthesis of novel benzimidazole derivatives as anti-tuberculosis agents

作　　者：张慧莹[1] 王彬[2] 盛莉[1] 李聃[1] 张东峰[1] 林紫云[1] 陆宇[2] 李燕[1] 黄海洪[1] 

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]首都医科大学附属北京胸科医院,北京市结核病胸部肿瘤研究所

出　　处：《药学学报》2014年第5期644-651,共8页Acta Pharmaceutica Sinica

摘　　要：脲基衍生物是最新报道的一类具有抗结核活性的化合物,其主要作用机制是通过抑制质膜转运子MmpL3,从而抑制结核杆菌细胞壁的合成。AU1235作为此系列的代表化合物,存在药代性质较差的问题。本文以AU1235为先导化合物,通过骨架跃迁策略设计并合成了一系列新型苯并咪唑衍生物,并进行体外抗结核活性测试。结果表明,2-氨基苯并咪唑类化合物8b在保留良好抗结核活性(MIC 0.03μg·mL-1)的同时,其代谢稳定性得到了改善,为进一步的结构优化提供了重要参考。In recent studies some urea derivatives have been identified as potent anti-tuberculosis agents by targeting mycobacterial membrane protein large 3 （MmpL3）. However, this compound series as exemplified by AU1235 exhibited poor in vitro pharmacokinetic profile. With AU1235 as the lead, we have identified a novel benzimidazole series as potential anti-tuberculosis agents by using scaffold hopping approach. Among these synthesized compounds, 2-aminobenzimidazole derivative 8b showed the potent anti-tuberculosis activity with the MIC value of 0.03 μg.mL-1. This compound also showed improved metabolic stability compared to AU1235. Our investigation indicated that benzimidazole derivatives are the promising lead for further optimization as anti-tuberculosis agents.

关 键 词：抗结核活性 AU1235 MmpL3 苯并咪唑衍生物 

分 类 号：R916[医药卫生—药学]