不同母核结构苦豆碱衍生物合成及其抗冠状病毒活性研究  

Synthesis and evaluation for anti-HCoV-OC43 activity of novel aloperine derivatives with different core structures

作　　者：孟润泽 公玥 施宇龙 王坤 彭宗根[1] 宋丹青[1] MENG Run-ze;GONG Yue;SHI Yu-long;WANG Kun;PENG Zong-gen;SONG Dan-qing(Institute of Pharmaceutical Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院,北京协和医学院医药生物技术研究所,北京100050

出　　处：《药学学报》2024年第2期404-412,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金(81974494);中国医学科学院医学与健康科技创新工程资助项目(2021-I2M-1-048)。

摘　　要：本研究设计合成了不同母核结构的12个全新苦豆碱衍生物,其中十元大环骨架苦豆碱衍生物3通过季铵盐γ-H的霍夫曼消除后扩环获得,结构经X-单晶确证。进而采用CCK-8法评价了目标物对抗人类β-冠状病毒HCoV-OC43的活性。结果显示,季铵盐苦豆碱2a与化合物3均具有良好活性,2a表现出最好抗病毒活性,EC50值为3.77μmol·L-1,SI值大于53.1。Schr?dinger分子对接结果显示,化合物2a与3均可能通过直接靶向宿主TMPRSS2和SR-B1发挥抗冠状病毒作用。研究结果拓展了桥环骨架苦豆碱的结构类型及其抗冠状病毒用途,为发展一类新型抗冠状病毒化合物提供了有益科学数据。In this study,we designed and synthesized 12 novel aloperine derivatives with different core structures.Among them,compound 3 with a ten-membered ring core was obtained through a special ring expansion reaction afterγ-H Huffman elimination of quaternary ammonium salt,and the structure was verified by X-single crystal diffraction.Furthermore,their antiviral activity against humanβ-coronavirus HCoV-OC43 was evaluated by CCK-8 assay.Quaternary ammonium salt 2a and 3 had a good inhibitory effect against HCoV-OC43,and 2a had the highest anti-HCoV-OC43 activity with an EC_(50)values of 3.77μmol·L~(-1)and a SI value of over 53.1.Schrdinger molecular docking results showed that both 2a and 3 might display their anti-HCoV-OC43 activity by directly acting on host TMPRSS2 and SR-B1.The results expanded the structural types of endocyclic aloperine and the function against coronavirus,and provided useful scientific data for the development of pharmaceutical applications of these compounds.

关 键 词：季铵盐苦豆碱 新型冠状病毒 十元环苦豆碱 TMPRSS2 SR-B1 

分 类 号：R914[医药卫生—药物化学]