2-[(喹啉-4-基)氨基]苯甲酸及其酰胺类化合物的设计、合成及抗流感活性研究  

Design,synthesis and anti-influenza activity of 2-[(quinoline-4-yl)amino]benzoic acid and 2-[(quinoline-4-yl)amino]benzamide derivatives

作　　者：艾昱辰 张德良 李阳[1] 王哲[1] 李先明 侯世澄 张超[1] 邵鹏柱[2] 胡春[1] AI Yuchen;ZHANG Deliang;LI Yang;WANG Zhe;LI Xianming;HOU Shicheng;ZHANG Chao;SHAW Pangchui;HU Chun(Key Laboratory of Structure-based Drug Design&Discovery(Ministry of Education),Shenyang Pharmaceutical University,Shenyang 110016,China;School of Life Sciences,The Chinese University of Hong Kong,Hong Kong SAR 999077,China)

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016 [2]香港中文大学生命科学学院,中国香港999077

出　　处：《中国药物化学杂志》2024年第5期339-350,共12页Chinese Journal of Medicinal Chemistry

基　　金：沈阳药科大学国家级大学生创新创业训练计划项目(202210163209)。

摘　　要：目的设计并合成一系列2-[(喹啉-4-基)氨基]苯甲酸及其酰胺类化合物,期望得到具有较好抗流感病毒活性的化合物。方法以芳香胺和乙氧基亚甲基丙二酸二乙酯为起始原料,经加成、环合、水解、脱羧、氯化和取代反应得到2-[(喹啉-4-基)氨基]苯甲酸,再与胺类化合物经缩合反应得到2-[(喹啉-4-基)氨基]苯甲酰胺类化合物,并评估目标化合物的细胞毒性、细胞病变保护活性和流感病毒抑制活性。结果设计并合成了15个2-[(喹啉-4-基)氨基]苯甲酸及其酰胺类化合物,结构经质谱(ESI-MS)和核磁共振氢谱(1H-NMR)确证。活性测试结果显示,部分化合物细胞毒性较低,并且不同程度地提高了MDCK细胞被流感病毒感染后的存活能力,其中化合物6a的抗流感病毒活性较好。结论部分2-[(喹啉-4-基)氨基]苯甲酸及其酰胺类化合物能够显著地提高MDCK细胞被流感病毒感染后的存活能力,且细胞毒性相对较小,具有相对较好的流感病毒抑制能力,具有进一步研究的价值。Influenza can cause severe respiratory diseases and seriously endanger human health.Nucleoprotein plays an important role in the replication,transcription and translation of influenza viruses and has been reported as a new drug target for anti-influenza drug design.Arg416 in the nucleoprotein tail loop can form a salt bridge interaction with Glu339 in another nucleoprotein monomer to ensure the normal generation of nucleoprotein oligomers as reported.Thus,we could design and synthesize compounds formed interaction with Glu339 to inhibit the interaction between Glu339 and Arg416.Then,the reproduction of influenza virus could not proceed normally.2-[(Quinoline-4-yl)amino]benzoic acid/2-[(quinoline-4-yl)amino]benzamide derivatives were designed according to the reported compounds.The results of molecular docking show that the target compounds after structural modification can interact well with Glu339 of nucleoprotein(PDB ID:2IQH).The cytotoxicity and anti-influenza virus activity of 15 target compounds were tested.The results of cytotoxicity assay,cytopathic effect assay and plaque inhibition assay show that most of the target compounds have low cytotoxicity and improve the viability of MDCK cells infected by influenza virus in varying degrees.Furthermore,compound 6a exhibits potent anti-influenza virus activity and is valuable for further research.

关 键 词：喹啉类化合物 核蛋白 流感病毒 合成 细胞毒性 抗流感病毒活性 

分 类 号：R914[医药卫生—药物化学]