title: Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus.
abstract: We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Shengwei
authors.initials: S
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Runfeng
authors.initials: R
authors.lastname: Li
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Haiming
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Yixia
authors.initials: Y
authors.lastname: Ling
authors.affiliation: State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors.forename: Zifeng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China. Electronic address: hu_wenhui@gibh.ac.cn.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects* / Q000235:genetics*; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects / Q000821:virology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; C000611547:pinanamine; C029899:imidazole
keywords: Dual inhibitory activity; Influenza A virus; M2 ion channel; Pinanamine derivatives