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Here, aminopyrimidine\/pyridine hydrazones were rationally designed through bioisosteric modification of lead compound L. Twenty-five derivatives were synthesized and evaluated, yielding multiple candidates with strong activity against major phytopathogenic fungi. Compound 4b-8 showed the best performance, with an EC50 of 0.3 \u03bcg\/mL against Monilinia fructicola and &amp;gt;90% in vivo control efficacy against peach brown rot at 50 \u03bcg\/mL, outperforming chlorothalonil. Mechanistic studies suggested that 4b-8 induces extensive ultrastructural damage, mitochondrial dysfunction, ATP depletion, and antioxidant system collapse in fungal hyphae. Transcriptomic profiling indicated substantial disruption of carbohydrate metabolism, particularly glucan-associated processes, which was consistent with the marked reduction in total \u03b2-glucan content. Collectively, the data demonstrate that 4b-8 exerts fungicidal activity through interference with glucan-related cellular processes, providing a promising lead with a mode of action distinct from commercial standards.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c00173","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T06:16:35Z","timestamp":1788243395000},"page":"27967-27977","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and Mechanistic\nInvestigation of Aminopyrimidine\/Pyridine\nHydrazone 4b-8 as a Potent Fungicide Candidate with Distinct\nGlucan-Associated Antifungal Mechanisms"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0572-094X","authenticated-orcid":true,"given":"Lei","family":"Zeng","sequence":"first","affiliation":[{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]},{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuotuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]},{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]},{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]},{"name":"Jiangxi Normal University , , , ,","place":["Nanchang, Jiangxi, P. R. China, 330022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-0402","authenticated-orcid":true,"given":"Meng","family":"Cai","sequence":"additional","affiliation":[{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]},{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-2794","authenticated-orcid":true,"given":"Hongwu","family":"He","sequence":"additional","affiliation":[{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. China, 430079"]},{"name":"Central China Normal University , , , ,","place":["Wuhan, Hubei, P. R. 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