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Among viral targets, the PA\u2013PB1 interface of the RNA polymerase complex has emerged as an attractive site for small\u2010molecule inhibition. Based on compound\n                    <jats:bold>1<\/jats:bold>\n                    , a previously identified PA\u2013PB1 interaction inhibitor featuring a cycloheptathiophene\u20103\u2010carboxamide scaffold, we designed and synthesized a new series of derivatives to investigate the role of the cycloheptyl moiety in antiviral activity and water solubility. In parallel, we developed an improved three\u2010step synthetic route to access 2\u2010amidothiophene\u20103\u2010carboxamide analogs more efficiently. The new derivatives (\n                    <jats:bold>2\u201316<\/jats:bold>\n                    ) provided valuable structure\u2013activity relationship insights, highlighting how modifications at C\u20105 influence both anti\u2010influenza potency and solubility. Among them, the C\u20105 phenyl analog\n                    <jats:bold>9<\/jats:bold>\n                    displayed the strongest antiviral activity, achieving sub\u2010micromolar EC\n                    <jats:sub>50<\/jats:sub>\n                    values (0.19\u20131.11\u2009\u00b5M) across a panel of influenza strains, along with a CC\n                    <jats:sub>50<\/jats:sub>\n                    value\u2009&gt;\u2009100\u2009\u00b5M. Notably, the C\u20105 methyl analog\n                    <jats:bold>5<\/jats:bold>\n                    showed the greatest enhancement in aqueous solubility (75.2\u2009\u00b5M) while maintaining low\u2010micromolar potency (EC\n                    <jats:sub>50<\/jats:sub>\n                    of 2\u2009\u00b5M) and no significant toxicity (CC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009&gt;\u2009100\u2009\u00b5M). Despite structural divergence from the starting hit\n                    <jats:bold>1<\/jats:bold>\n                    , both compounds preserved the PA\u2013PB1 interaction inhibition mechanism, as demonstrated by enzyme\u2010linked immunosorbent assay (ELISA) and supported by docking studies within the PA\n                    <jats:sub>C<\/jats:sub>\n                    cavity.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70314","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T04:20:17Z","timestamp":1779510017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Streamlined Synthesis and Structure\u2013Activity Relationship Analysis of 2\u2010Amidothiophene\u20103\u2010Carboxamides Targeting Influenza Polymerase PA\u2010PB1 Heterodimerization"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9369-8564","authenticated-orcid":false,"given":"Tommaso","family":"Felicetti","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Zago","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Padua  Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3337-2372","authenticated-orcid":false,"given":"Andrea","family":"Astolfi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Perugia  Perugia 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