Design, Synthesis, and Antifungal Activity of NovelOxadiazole–Pyrazole–Triazole Derivatives: Insights intoCellular Disruption Revealed by Integrated Transcriptomic and ProteomicAnalyses

Resistance to single-target fungicides necessitates structurally innovative antifungal agents with broadened modes of action. Herein, a series of pyrazole–oxadiazole-linked 1,2,4-triazole derivatives (L1–L39) were designed and synthesized via molecular hybridization. Compound L22 exhibited exceptional activity against Magnaporthe grisea (EC50 = 5.96 μg/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–oxadiazole–triazole derivatives as potent, safe, and mechanistically distinct antifungal leads, warranting further development for agricultural disease management.