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Most commercially available antiviral agents function primarily as protectants. However, the long\u2010term and repetitive application of conventional broad\u2010spectrum antiviral agents has led to the emergence of resistance, diminishing their field efficacy. To discover new antiviral drugs, we designed and synthesized 31 novel ribavirin derivatives incorporating cinnamic acid motifs\n                      <jats:italic>via<\/jats:italic>\n                      a lead optimization strategy and evaluated their anti\u2010tobacco mosaic virus (TMV) activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Biological assays revealed that compound\n                      <jats:bold>A23<\/jats:bold>\n                      exhibited potent protective activity against TMV, with an EC\u2085\u2080 of 131.1\u2009\u03bcg\/mL, which was significantly lower than that of ribavirin (529.9\u2009\u03bcg\/mL) and ningnanmycin (248.4\u2009\u03bcg\/mL). Further research indicated that compound\n                      <jats:bold>A23<\/jats:bold>\n                      significantly enhanced the activity of defense\u2010related enzymes and regulated the plant hormone signal transduction pathway as well as the plant\u2010pathogen interaction pathway in tobacco plants. Notably, it upregulated the expression of key genes\n                      <jats:italic>NPR1<\/jats:italic>\n                      and\n                      <jats:italic>PR\u20101<\/jats:italic>\n                      in the salicylic acid (SA) signaling pathway, thereby effectively enhancing the plant's defense response and resistance against TMV.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      These results demonstrate that compound\n                      <jats:bold>A23<\/jats:bold>\n                      possesses remarkable bioactivity and effectively controls TMV infection by inducing host plant immunity. Its promising efficacy supports its potential as a candidate agent for controlling plant viral diseases and warrants further investigation. \u00a9 2025 Society of Chemical Industry.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ps.70462","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T10:21:45Z","timestamp":1766398905000},"page":"3439-3451","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel cinnamic acid\u2010ribavirin conjugates: design, synthesis, antiviral activity against tobacco mosaic virus and mechanistic study"],"prefix":"10.1002","volume":"82","author":[{"given":"Min","family":"Luo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Green Pesticide Center for R&amp;D of Fine Chemicals of Guizhou University  Guiyang 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