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To solve this agricultural crisis, novel tetrazolinone-pyrazine derivatives were rationally designed and synthesized by integrating potentially resistance-breaking tetrazolinone toxophore with a pyrazine scaffold via oxime ether linkage. Bioassays revealed that compound 19 exhibited exceptional in vitro activity against Sclerotinia sclerotiorum with an EC50 of 0.003 mg\/L, greatly exceeding the commercial QoI metyltetraprole (EC50 = 0.13 mg\/L). In vivo assays on Brassica napus L. leaves confirmed its excellent curative (95.4%) and protective (93.6%) efficacies at 200 mg\/L. Scanning electron microscopy detected severe hyphal morphological disruption. Transcriptomic profiling and qRT-PCR verified that compound 19 markedly disturbed fungal energy cycles, redox homeostasis and secondary metabolite biosynthesis. Molecular docking and MM-GBSA calculations confirmed its strong binding affinity for wild-type and G143A-mutated cytochrome bc1 complexes. This work identifies compound 19 as a promising next-generation agrochemical for resistant phytopathogenic fungal management.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c09709","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T07:01:14Z","timestamp":1789023674000},"page":"29169-29179","source":"Crossref","is-referenced-by-count":0,"title":["Rational Design\nof Novel Tetrazolinone-Pyrazine Derivatives:\nSynthesis, Antifungal Activity, and Mechanism of Action"],"prefix":"10.1021","volume":"74","author":[{"given":"Zixian","family":"Wang","sequence":"first","affiliation":[{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9123-3384","authenticated-orcid":true,"given":"Zili","family":"Ren","sequence":"additional","affiliation":[{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-5538","authenticated-orcid":true,"given":"Jiawang","family":"Wang","sequence":"additional","affiliation":[{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3653-3450","authenticated-orcid":true,"given":"Haiqun","family":"Cao","sequence":"additional","affiliation":[{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8731-1068","authenticated-orcid":true,"given":"Quan","family":"Gao","sequence":"additional","affiliation":[{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , ,","place":["Hefei, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"2026092310075208400_cit1","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1002\/ps.520","article-title":"The strobilurin fungicides","volume":"58","author":"Bartlett","year":"2002","journal-title":"Pest\nManag. 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