title: Discovery and SAR study of piperidine-based derivatives as novel influenza virus inhibitors.
abstract: A series of piperidine-based derivatives were identified as novel and potent inhibitors of the influenza virus through structural modification of a compound that was selected from a high-throughput screen. Various analogues were synthesized and confirmed as inhibitors. The structure–activity relationship (SAR) studies suggested that the ether linkage between the quinoline and piperidine is critical for the inhibitory activity. The optimized compound tert-butyl 4-(quinolin-4-yloxy)piperidine-1-carboxylate 11e had an excellent inhibitory activity against influenza virus infection from a variety of influenza virus strains, with EC50 values as low as 0.05 μM. The selectivity index value (SI = MLD50/EC50) of 11e is over 160000 based on cytotoxicity, measured by MTT assays of three cell lines. We carried out a time-of-addition experiment to delineate the mechanism of inhibition. The result indicates that 11e interferes with the early to middle stage of influenza virus replication.
authors.affiliation: Key Laboratory of Structural Biology and Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China. wanggx@pkusz.edu.cn zyang@pku.edu.cn mluo@gsu.edu.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wang
authors.forename: Longjian
authors.initials: L
authors.lastname: Chen
authors.forename: Tongmei
authors.initials: T
authors.lastname: Xian
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liang
authors.forename: Xintao
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Luo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009975:Orthomyxoviridae / Q000187:drug effects*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D010880:Piperidines; C032727:piperidine