药学学报, 2019, 54(9): 1627-1635
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.

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
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
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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