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Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors
Author(s) -
Wu Shuwen,
Huang Jing,
Gazzarrini Sabrina,
He Si,
Chen Lihua,
Li Jun,
Xing Li,
Li Chufang,
Chen Ling,
Neochoritis Constantinos G.,
Liao George P.,
Zhou Haibing,
Dömling Alexander,
Moroni Anna,
Wang Wei
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500318
Subject(s) - amantadine , influenza a virus , mutant , ec50 , virology , chemistry , potency , virus , cytotoxicity , structure–activity relationship , influenza a virus subtype h5n1 , pharmacology , biology , in vitro , biochemistry , gene
Basic bulky amines such as amantadine are well‐characterized M2 channel blockers, useful for treating influenza. Herein we report our surprising findings that charge‐neutral, bulky isocyanides exhibit activities similar to—or even higher than—that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The −NH 2 to −N≡C group replacement within current anti‐influenza drugs was found to give compounds with high activities at low‐micromolar concentrations. For example, a tenfold improvement in potency was observed for 1‐isocyanoadamantane ( 27 ), with an EC 50 value of 0.487 μ m against amantadine‐sensitive H5N1 virus as determined by both MTT and plaque‐reduction assays, without showing cytotoxicity. Furthermore, the isocyanide analogues synthesized in this study did not inhibit the V27A or S31N mutant M2 ion channels, according to electrophysiology experiments, and did not exhibit activity against amantadine‐resistant virus strains.