药学学报, 2019, 54(9): 1627-1635
引用本文:
范田运, 杨元帅, 胡辛欣, 汪燕翔, 游雪甫, 宋丹青. 全新骨架环化小檗碱衍生物抗MRSA活性研究[J]. 药学学报, 2019, 54(9): 1627-1635.
FAN Tian-yun, YANG Yuan-shuai, HU Xin-xin, WANG Yan-xiang, YOU Xue-fu, SONG Dan-qing. Anti-MRSA activities of cycloberberine derivatives with a novel chemical scaffold[J]. Acta Pharmaceutica Sinica, 2019, 54(9): 1627-1635.

全新骨架环化小檗碱衍生物抗MRSA活性研究
范田运, 杨元帅, 胡辛欣, 汪燕翔, 游雪甫, 宋丹青
中国医学科学院、北京协和医学院医药生物技术研究所, 北京市抗感染重点实验室, 北京 100050
摘要:
本研究基于课题组前期工作,以自主构建的环化小檗碱为母核,继续延伸设计合成了15个不同结构类型的全新环化小檗碱衍生物,并通过革兰氏阳性菌的测定,丰富了此类化合物的构效关系:① C环为必需片段;② 7,8-和8,13-双取代衍生物活性弱于相应单取代衍生物或者相当。化合物9a对临床棘手的耐甲氧西林金黄葡球菌/中介耐万古霉素金黄葡球菌菌株活性明显优于左氧氟沙星,MIC值达1~2 μg·mL-1。体外代谢实验表明9a对血浆和肝微粒体的稳定性良好。分子对接显示其可能通过靶向细菌Topo IV的ParE亚基发挥抗MRSA活性,与临床现有抗菌药作用位点均不同。本研究结果为此类化合物发展成一类新型抗MRSA化合物提供了重要的科学数据。
关键词:    环化小檗碱      抗菌活性      MRSA      构效关系      分子对接<     
Anti-MRSA activities of cycloberberine derivatives with a novel chemical scaffold
FAN Tian-yun, YANG Yuan-shuai, HU Xin-xin, WANG Yan-xiang, YOU Xue-fu, SONG Dan-qing
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Using CBBR as the parent core constructed in our lab, we designed and synthesized 15 novel compounds with diverse structures for evaluation of anti-bacterial activities. Structure activity relationship studies revealed that ① ring C was essential for the activity; ② 7,8-or 8,13-disubstituted CBBR derivatives showed ideal activities, weaker or similar to those corresponding to 7-, 8-, or 13-monosubstituted CBBR derivatives. Among those, compound 9a showed the most potential activity against MRSA/VISA isolates with MIC values of 1-2 μg·mL-1, much better than Lev. 9a also displayed higher stability in the plasma and liver microsomes. Molecular docking indicated that 9a might target bacterial DNA Topo IV ParE subunit, indicating a mode of action distinct from current antibacterial drugs on market. The results provided key scientific evidence for developing such compounds into a new family of anti-MRSA drugs.
Key words:    cycloberberine    antibacterial    MRSA    structure-activity relationship    molecular dock   
收稿日期: 2019-06-19
DOI: 10.16438/j.0513-4870.2019-0485
基金项目: 中国医学科学院医学与健康科技创新工程资助项目(2019-12M-1-005);北京市自然科学基金资助项目(7172136).
通讯作者: 宋丹青,Tel/Fax:86-10-63165268,E-mail:songdanqingsdq@hotmail.com
Email: songdanqingsdq@hotmail.com
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