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.
作者
孟润泽
公玥
施宇龙
王坤
彭宗根
宋丹青
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)
出处
《药学学报》
CAS
CSCD
北大核心
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)。
