Design, synthesis, and quantitative structure‐antifungal activity relationship of 1,2,4‐oxadiazole‐containing mappicine derivatives against phytopathogenic fungi

Abstract BACKGROUND Fungal diseases in crops have become a growing major threat to global agriculture, causing substantial yield and economic losses. To address the critical demand for effective antifungal agents against phytopathogenic fungi, a series of mappicine derivatives incorporating a 1,2,4‐oxadiazole moiety were rationally designed and synthesized in this study using an active substructure fusion strategy, followed by systematic evaluation of their antifungal potential. RESULTS Bioassay results revealed that most derivatives exhibited broad‐spectrum and potent antifungal activity, with exceptional efficacy against Rhizoctonia solani ( R. solani ). Among them, compound M‐25 displayed the strongest antifungal activity against R. solani with an EC 50 value of 4.52 μg/mL, making it approximately 5.8 times more potent than the positive control azoxystrobin (EC 50 = 26.14 μg/mL). Further in vivo assessments demonstrated that M‐25 provided protective (70.2%) and curative (33.0%) efficacy against R. solani , comparable to that of azoxystrobin (69.1 and 39.0%, respectively). Quantitative structure–activity relationship (QSAR) modeling indicated that electronegativity and electronic effects critically influence antifungal activity. Mechanistic studies revealed that the primary antifungal mechanism against R. solani involved the severe disruption of mycelial morphology, the loss of cell membrane integrity, and the accumulation of intracellular reactive oxygen species. CONCLUSION This study offers valuable insights for the development of mappicine‐based antifungal agents for plant protection. © 2026 Society of Chemical Industry.