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Herein we report our surprising findings that charge\u2010neutral, bulky isocyanides exhibit activities similar to\u2014or even higher than\u2014that of amantadine. We also demonstrate that these isocyanides have potent growth inhibitory activity against the H5N1 virus. The \u2212NH<jats:sub>2<\/jats:sub> to \u2212N\u2261C group replacement within current anti\u2010influenza drugs was found to give compounds with high activities at low\u2010micromolar concentrations. For example, a tenfold improvement in potency was observed for 1\u2010isocyanoadamantane (<jats:bold>27<\/jats:bold>), with an EC<jats:sub>50<\/jats:sub> value of 0.487\u2005\u03bc<jats:sc>m<\/jats:sc> against amantadine\u2010sensitive H5N1 virus as determined by both MTT and plaque\u2010reduction 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\u2010resistant virus strains.<\/jats:p>","DOI":"10.1002\/cmdc.201500318","type":"journal-article","created":{"date-parts":[[2015,9,7]],"date-time":"2015-09-07T06:42:22Z","timestamp":1441608142000},"page":"1837-1845","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Isocyanides as Influenza\u2005A Virus Subtype H5N1 Wild\u2010Type M2 Channel Inhibitors"],"prefix":"10.1002","volume":"10","author":[{"given":"Shuwen","family":"Wu","sequence":"first","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis &amp; Drug Discovery Ministry of Education School of Pharmaceutical Sciences Wuhan University  Wuhan 430071 P.R.\u2005China"},{"name":"State Key Laboratory of Virology of China Wuhan University  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