Citral‐derived 1,4‐dihydropyridine/pyridine antifungal leads: multitarget disruption of the cellular barrier, energy metabolism, and redox homeostasis in Fusarium graminearum

BACKGROUND Plant diseases pose a persistent threat to agricultural and forestry production, while the extensive use of conventional fungicides has promoted resistance development and raised environmental residue concerns. Therefore, developing plant essential oil‐derived antifungal leads with novel modes of action represents a promising strategy for sustainable disease management. RESULTS A series of citral‐derived 1,4‐dihydropyridine (1,4‐DHP) and pyridine derivatives C1–C12 and D1–D10 were designed and synthesized. Among them, compound C1 showed the most potent antifungal activity, with a half‐maximal effective concentration (EC 50 ) value of 1.88 mg L −1 against Fusarium graminearum , which was superior to carbendazim (EC 50 = 2.70 mg L −1 ). The in vivo experiments showed that compound C1 at 200 mg L −1 achieved protective and curative effects against F. graminearum at 77.91% and 95.70%, which were equipotent to carbendazim. Notably, compound C1 exhibited higher pH stability than citral under the tested acid–base conditions. Structure–activity relationship analysis suggested that short‐chain alkyl substitution was favorable for improving antifungal activity. Transcriptomic, morphological, and physiological and biochemical analyses revealed that compound C1 exerted its antifungal activity by disrupting cell membrane integrity and cellular ultrastructure, suppressing mitochondrial energy metabolism, and disturbing redox homeostasis in F. graminearum . Molecular docking suggested that the 1,4‐DHP ring and ester groups are key structural features facilitating target binding and the antifungal activity of compound C1. Moreover, compound C1 exhibited limited cytotoxicity toward LO2 and HEK293 cells at 10 mg L −1 , moderate acute toxicity to zebrafish, and low predicted bioconcentration potential. CONCLUSION Compound C1 shows promise as a multi‐targeted antifungal lead for the green management of Fusarium head blight (FHB). © 2026 Society of Chemical Industry.