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We here report the identification of a class of 4\u2010<jats:italic>tert<\/jats:italic>\u2010butylphenyl\u2010substituted spirothiazolidinones as HA\u2010mediated fusion inhibitors with specific activity against influenza A\/H3N2 virus. The novel spirocyclic compounds were achieved by using one\u2010pot cyclocondensation method and the chemical structures were characterized by IR, <jats:sup>1<\/jats:sup>H NMR, <jats:sup>13<\/jats:sup>C NMR, and elemental analysis. Compound <jats:bold>2c<\/jats:bold>, bearing methyl substitutions at positions 2\u2010 and 8\u2010 of the spiro ring displayed an EC<jats:sub>50<\/jats:sub> value against influenza A\/H3N2 virus of 1.3\u2009\u03bcM and an antiviral selectivity index of 30. The fusion\u2010inhibiting effect of compound <jats:bold>2c<\/jats:bold> was revealed in the polykaryon assay which is based on cell\u2010cell fusion when influenza virus H3 HA\u2010transfected cells are exposed to low pH. Computer\u2010aided docking was performed to predict the possible binding pocket in the H3 HA trimer. Resistance data and <jats:italic>in silico<\/jats:italic> studies indicated that compound <jats:bold>2c<\/jats:bold> has an overlapping binding pocket in the stem region of H3 HA with the known fusion inhibitors TBHQ and arbidol.<\/jats:p>","DOI":"10.1002\/ddr.70080","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T14:07:44Z","timestamp":1742825264000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Design, Synthesis and Anti\u2010Influenza Virus Activity of 4\u2010<i>Tert<\/i>\u2010Butyl\u2010<i>N<\/i>\u2010(3\u2010Oxo\u20101\u2010Thia\u20104\u2010Azaspiro[4.5]Dec\u20104\u2010yl)Benzamide Derivatives That Target Hemagglutinin\u2010Mediated Fusion"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0309-663X","authenticated-orcid":false,"given":"G\u00f6zde","family":"\u00c7\u0131nar","sequence":"first","affiliation":[{"name":"Institute of 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