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Phenamacril, a myosin I-targeting fungicide, has a limited antifungal spectrum. Using structure-based drug design focusing on M375 in Fusarium graminearum myosin I (FgMyoI), we synthesized 25 phenamacril derivatives. The II-2 emerged as the most potent inhibitor (EC50 = 0.0077 mg\/L against F. graminearum), with broad-spectrum activity against various phytopathogens. Biochemical and computational analyses confirmed that II-2 tightly binds FgMyoI and inhibits its ATPase activity. In vivo tests demonstrated excellent protective and curative efficacy against FHB in wheat and corn, while toxicity assays revealed low risk to nontarget organisms. These results identify II-2 as a promising myosin inhibitor and a novel candidate for FHB management. This work also provides a foundation for the rational design of myosin-targeting fungicides against diverse plant fungal diseases.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c07803","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:02:14Z","timestamp":1786554134000},"page":"26115-26132","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of Novel\nCyanoacrylates as Potential Myosin\nI Inhibitors with Remarkable Activity against\n                    <i>Fusarium<\/i>\n                    Species"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1601-0373","authenticated-orcid":true,"given":"Songtao","family":"Liu","sequence":"first","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]},{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyang","family":"Yang","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Yang","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linwei","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianshan","family":"Li","sequence":"additional","affiliation":[{"name":"Hebei University , , ,","place":["Baoding, China, 071002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Jiangsu Academy of Agricultural Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renkai","family":"Lei","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulan","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Geng","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Chu","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangyang","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6655-9478","authenticated-orcid":true,"given":"Shu","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Song","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7349-0686","authenticated-orcid":true,"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Feng","sequence":"additional","affiliation":[{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Yan","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3235-2406","authenticated-orcid":true,"given":"Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Province and Chinese Academy of Sciences , , ,","place":["Nanjing, China, 210014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 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Sci."},{"key":"2026090104475161900_cit17","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1094\/PDIS-10-13-1051-RE","article-title":"Triazole sensitivity\nin a contemporary population of Fusarium graminearum from New York wheat and competitiveness of a tebuconazole-resistant\nisolate","volume":"98","author":"Spolti","year":"2014","journal-title":"Plant Dis."},{"key":"2026090104475161900_cit18","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1002\/ps.5675","article-title":"Resistance risk assessment\nfor Fusarium graminearum to pydiflumetofen,\na new succinate dehydrogenase inhibitor","volume":"76","author":"Sun","year":"2020","journal-title":"Pest\nManage. Sci."},{"key":"2026090104475161900_cit19","doi-asserted-by":"publisher","DOI":"10.1038\/srep08248","article-title":"Whole-genome sequencing reveals that mutations\nin myosin-5 confer resistance to the fungicide phenamacril in Fusarium graminearum","volume":"5","author":"Zheng","year":"2015","journal-title":"Sci.\nRep."},{"key":"2026090104475161900_cit20","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.cropro.2007.04.010","article-title":"JS399\u201319, a new\nfungicide against wheat scab","volume":"27","author":"Li","year":"2008","journal-title":"Crop Prot."},{"key":"2026090104475161900_cit21","doi-asserted-by":"publisher","first-page":"15653","DOI":"10.1021\/acs.jafc.4c03467","article-title":"Unveiling the mechanism of phenamacril resistance\nin F. graminearum: computational and\nexperimental insights into the C423A mutation in FgMyoI","volume":"72","author":"Bao","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"2026090104475161900_cit22","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1242\/jcs.094300","article-title":"The myosin superfamily at a glance","volume":"125","author":"Hartman","year":"2012","journal-title":"J. Cell Sci."},{"key":"2026090104475161900_cit23","doi-asserted-by":"publisher","first-page":"3675","DOI":"10.1021\/jm200259f","article-title":"Inhibition of Myosin\nATPase activity by halogenated pseudilins: a structure-activity study","volume":"54","author":"Preller","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026090104475161900_cit24","doi-asserted-by":"publisher","first-page":"4750","DOI":"10.1091\/mbc.e07-02-0127","article-title":"Myosin VI is required\nfor targeted membrane transport during cytokinesis","volume":"18","author":"Arden","year":"2007","journal-title":"Mol. Biol. 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Opin.\nCell Biol."},{"key":"2026090104475161900_cit30","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/nsmb908","article-title":"The structural basis of blebbistatin\ninhibition and specificity for myosin II","volume":"12","author":"Allingham","year":"2005","journal-title":"Nat.\nStruct. Mol. Biol."},{"key":"2026090104475161900_cit31","doi-asserted-by":"publisher","first-page":"29700","DOI":"10.1074\/jbc.M111.239210","article-title":"Mechanism and specificity\nof pentachloropseudilin-mediated inhibition of myosin motor activity","volume":"286","author":"Chinthalapudi","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2026090104475161900_cit32","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1111\/1462-2920.12711","article-title":"A small molecule species\nspecifically inhibits Fusarium myosin I","volume":"17","author":"Zhang","year":"2015","journal-title":"Environ. 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Sci."},{"key":"2026090104475161900_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jscs.2024.101928","article-title":"Design, synthesis, and\nantifungal activity of novel cyanoacrylate derivatives containing\na naphthalene moiety as potential myosin-5 inhibitor","volume":"28","author":"Jin","year":"2024","journal-title":"J. Saudi Chem. Soc."},{"key":"2026090104475161900_cit38","doi-asserted-by":"publisher","first-page":"20664","DOI":"10.1021\/acs.jafc.5c01840","article-title":"Synthesis and antifungal\nactivity evaluation of novel 2-cyanoacrylate derivatives containing\narylamide moiety as potential Myosin-5 inhibitors","volume":"73","author":"Hou","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"2026090104475161900_cit39","doi-asserted-by":"publisher","DOI":"10.1007\/s44297-024-00034-z","article-title":"A novel\nhighly antifungal compound ZJS-178\ntargeting myosin I inhibits the endocytosis and mycotoxin biosynthesis\nof Fusarium graminearum","volume":"2","author":"Chen","year":"2024","journal-title":"Crop Health"},{"key":"2026090104475161900_cit40","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA\nmethods to estimate ligand-binding affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discovery"},{"key":"2026090104475161900_cit41","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development\nand testing\nof a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Chem. 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