新型苯并咪唑衍生物的设计、合成和抗结核活性研究

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

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 0.03 μg·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。

Abstract: 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.