2-芳基取代苯并硫代吡喃酮类化合物的设计、合成及其抗结核活性研究  

Design, synthesis and antituberculosis activity of 2-aryl substituted benzothiopyranone compounds

作　　者：唐霞霞 李文艺 李鹏[1] 王彬[2] 陆宇[2] 黄海洪 李刚 TANG Xia-xia;LI Wen-yi;LI Peng;WANG Bin;LU Yu;HUANG Hai-hong;LI Gang(Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research,Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Beijing Key Laboratory of Drug Resistance Tuberculosis Research,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing 101149,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,中国医学科学院抗耐药结核创新药物研究重点实验室,活性物质发现与适药化研究北京市重点实验室,北京100050 [2]北京市结核病胸部肿瘤研究所,耐药结核病研究北京市重点实验室,北京101149

出　　处：《药学学报》2024年第4期987-996,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82373711);中国医学科学院中央级公益性科研院所基本科研业务费专项资金资助(2018PT35026).

摘　　要：本研究基于前期获得的具有显著抗结核活性的苯并硫代吡喃酮骨架,设计合成了一系列2位芳基取代的苯并硫代吡喃酮类化合物,并对其进行抗结核活性及初步成药性评价。结果表明,大多数化合物对结核分枝杆菌H37Rv具有良好的抑制活性,其中化合物8g、8h、8q和9f的抗结核活性较强(MIC=0.2~0.4μg·mL^(-1))。另外,活性化合物无明显细胞毒性和心脏毒性风险,化合物8h和8q具有良好的肝微粒体代谢稳定性,对肝药酶CYP 3A4/5和CYP 2C9无明显抑制作用,适用于结核病治疗的联合用药方案。A novel series of 2-aryl substituted benzothiopyranone compounds was designed and synthesized based on our previously obtained benzothiopyranone scaffold with significant antituberculosis activity.All target compounds were evaluated for their antimycobacterial activity and preliminary druggability was subsequently investigated for some selected compounds with good activity.The results indicated that most compounds showed good activity against Mycobacterium tuberculosis H37Rv.Among them,compounds 8g,8h,8q and 9f showed potent activity with MIC ranged from 0.2 to 0.4μg·mL^(-1).Furthermore,some active compounds exhibited low cytotoxicity and cardiotoxicity risk.It is worth noting that compounds 8h and 8q with good liver microsome stability and low inhibition of CYPs 3A4/5 and 2C9 were suitable for combination drug regimen to treat tuberculosis.

关 键 词：2-芳基取代苯并硫代吡喃酮 设计合成 抗结核活性 初步成药性评价 

分 类 号：R914[医药卫生—药物化学]