Design, biological evaluation, and 3D ‐ QSAR analysis of fusaric acid derivatives as antifungal agents against plant pathogens

Abstract BACKGROUND Fusaric acid (FA), a non‐host‐selective toxin with antifungal and insecticidal activities, has attracted attention as a promising lead structure for developing novel agrofungicides. This study aimed to design and synthesize FA derivatives with improved antifungal activity and reduced phytotoxicity, and to investigate their antifungal mechanism and structure–activity relationships. RESULTS A series of FA derivatives were synthesized and evaluated against six major plant pathogenic fungi, including Magnaporthe oryzae . Several derivatives showed enhanced antifungal activity compared with the previously identified scaffold H52 , and 10 compounds completely inhibited M. oryzae at 100 μg mL −1 under in vitro conditions. The most active derivatives exhibited half‐maximal effective concentration (EC 50 ) values of 6.09–9.84 μg mL −1 . Phytotoxicity assays showed that compounds A6 , A10 , A12 , B4 , B6 , and B7 had safety profiles comparable to the commercial fungicide azoxystrobin. Compound B4 further demonstrated concentration‐dependent protective activity against rice blast under pot conditions, reducing the disease index from approximately 66.7 in the untreated control to about 14.8 at the highest tested concentration. Mechanistic studies revealed severe hyphal deformation, cell wall disruption, intracellular leakage, and reactive oxygen species (ROS) accumulation following B4 treatment. A comparative molecular field analysis‐based three‐dimensional quantitative structure–activity relationship (3D‐QSAR) model exhibited strong predictive performance ( q 2 = 0.69, r 2 = 0.992), indicating reliable structure–activity relationships. Contour map analysis suggested that bulky substituents near the core ring and electron‐withdrawing groups in specific regions significantly enhance antifungal activity. CONCLUSION FA derivatives can be rationally optimized to improve antifungal activity, reduce phytotoxicity, and be effective in planta disease control, providing promising candidates and design strategies for next‐generation agrofungicides. © 2026 Society of Chemical Industry.