title: Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors.
abstract: The adamantanes are a class of anti-influenza drugs that inhibit the M2 ion channel of the influenza A virus. However recently, the clinical effectiveness of these drugs has been called into question due to the emergence of adamantane-insensitive A/M2 mutants. Although we previously reported (1R,2R,3R,5S)-3-pinanamine 3 as a novel inhibitor of the wild type influenza A virus M2 protein (WT A/M2), limited inhibition was found for adamantane-resistant M2 mutants. In this study, we explored whether newly synthesized pinanamine derivatives were capable of inhibiting WT A/M2 and selected adamantane-resistant M2 mutants. Several imidazole and guanazole derivatives of pinanamine were found to inhibit WT A/M2 to a comparable degree as amantadine and one of these compounds 12 exhibits weak inhibition of A/M2-S31N mutant and it is marginally more effective in inhibiting S31NM2 than amantadine. This study provides a new insight into the structural nature of drugs required to inhibit WT A/M2 and its mutants.
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Yanling
authors.initials: Y
authors.lastname: Jie
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Rosenberg
authors.forename: Junting
authors.initials: J
authors.lastname: Wan
authors.forename: Shaogao
authors.initials: S
authors.lastname: Zeng
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Yiping
authors.initials: Y
authors.lastname: Xiao
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Marco G
authors.initials: MG
authors.lastname: Casarotto
authors.forename: Wenhui
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors*; D010948:Viral Plaque Assay; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D007473:Ion Channels; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins