新型神经氨酸酶抑制剂的设计合成及抗流感病毒活性  

Design,Synthesis and Anti-influenza Activities of Novel Neuraminidase Inhibitors

作　　者：尤义鹏 聂林 刘晋彪[1] 丰亚辉 鲁桂[1] YOU Yipeng;NIE Lin;LIU Jinbiao;FENG Yahui;LU Gui(School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China)

机构地区：[1]中山大学药学院,广州510006

出　　处：《高等学校化学学报》2020年第10期2279-2286,M0004,共9页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:81972824);广东省自然科学基金(批准号:2020A1515011513)资助.

摘　　要：对上市药物扎那米韦、奥司他韦和帕拉米韦进行结构修饰,对化合物相应的氨基进行磷酰化,设计合成了10个新化合物.新化合物在酶水平和细胞水平均具有一定的抗流感病毒活性,化合物I-8在酶水平、化合物I-6在细胞水平具有和阳性对照药奥司他韦相当的活性.Based on the X-ray crystal structure of neuraminidase(NA),we chosed zanamivir,oseltamivir and peramivir as lead compounds,introduced phosphate ester groups to the corresponding amino group,and obtained ten new phosphamide derivatives,including C4 phosphorylated compounds of zanamivir and perami⁃vir precursor,C5 phosphorylated compounds of oseltamivir.Their structures were confirmed by means of nu⁃clear magnetic resonance spectroscopy(NMR)and high resolution mass spectrometry(HRMS).Molecular dy⁃namics simulations were used to evaluate the interaction of new compounds with NA.Moreover,their abilities to inhibit neuraminidase and influenza viruses were tested.The preliminary results revealed that most new com⁃pounds possessed antiviral activities both in enzyme and cell levels.In particular,compound I-8 showed com⁃parable inhibitory activities to oseltamivir with the half maximal inhibitory concentration(IC50)value of 0.397 nmol/L on NA-sensitive enzyme(NAs),while compound I-6 showed comparable inhibitory activities to oselta⁃mivir with the IC50 value of 0.121μmol/L on influenza A H3N2,which might be the candidate compounds for further development.Our work might provide some insight into the rational design of anti-flu agents and the dis⁃covery of new effective drugs.

关 键 词：磷酰化 神经氨酸酶抑制剂 抗流感病毒 

分 类 号：R914.5[医药卫生—药物化学]