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Herein, a series of pyrazole\u2013oxadiazole-linked 1,2,4-triazole derivatives (L1\u2013L39) were designed and synthesized via molecular hybridization. Compound L22 exhibited exceptional activity against Magnaporthe grisea (EC50 = 5.96 \u03bcg\/mL), outperforming the commercial fungicide isoprothiolane, and potently inhibited Botrytis cinerea and Verticillium dahliae. In vivo assays confirmed its excellent protective and curative efficacies against rice blast. Mechanistic investigations revealed that L22 induces severe cellular disruption, characterized by compromised membrane integrity, cell wall deformation, and broad dysregulation of sterol\/lipid metabolism, carbohydrate utilization, mitochondrial respiration, and stress-response pathways. Furthermore, L22 displayed no detectable phytotoxicity toward rice seedlings at effective concentrations. These findings establish pyrazole\u2013oxadiazole\u2013triazole derivatives as potent, safe, and mechanistically distinct antifungal leads, warranting further development for agricultural disease management.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c01107","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T17:02:02Z","timestamp":1786035722000},"page":"24937-24948","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Antifungal Activity of Novel\nOxadiazole\u2013Pyrazole\u2013Triazole Derivatives: Insights into\nCellular Disruption Revealed by Integrated Transcriptomic and Proteomic\nAnalyses"],"prefix":"10.1021","volume":"74","author":[{"given":"Fa-li","family":"Wang","sequence":"first","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3693-4481","authenticated-orcid":true,"given":"Xiao-li","family":"Ren","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Gao","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Ruan","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-mei","family":"Yao","sequence":"additional","affiliation":[{"name":"Guizhou Provincial Academy of Agricultural Sciences , , ,","place":["Guiyang, China, 550006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-hua","family":"Liu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Hangzhou, China, 310018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-kun","family":"Li","sequence":"additional","affiliation":[{"name":"Southwest University , , ,","place":["Chongqing, China, 400715"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2531-1038","authenticated-orcid":true,"given":"Dan-dan","family":"Xie","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wikum Harshana","family":"Jayasinghe","sequence":"additional","affiliation":[{"name":"University of Peradeniya , , ,","place":["Peradeniya, Sri Lanka, 20400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2210-3831","authenticated-orcid":true,"given":"Lin-hong","family":"Jin","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-5225","authenticated-orcid":true,"given":"Xia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for R&D of Fine Chemicals of Guizhou University , , ,","place":["Guiyang, China, 550025"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"issue":"6","key":"2026081910154199300_cit1","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/s43016-020-0075-0","article-title":"Threats to global food security from emerging fungal\nand oomycete crop pathogens","volume":"1","author":"Fones","year":"2020","journal-title":"Nat. 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