Discovery of natural paeonol derivatives containing diphenyl ether as potent fungicide candidates

Abstract BACKGROUND Natural products such as paeonol and diphenyl ethers are valuable sources for lead compound discovery in agrochemical research. RESULTS To develop novel antifungal agents, 22 2‐phenoxybenzoate derivatives were rationally designed and synthesized via ester bridging based on the active substructure splicing strategy, and their antifungal activities were evaluated. Among these compounds, compound 6r exhibited good antifungal activity with a half‐maximal effective concentration (EC 50 ) value of 3.05 mg/L. It was 1.56‐fold more potent than the commercial fungicide chlorothalonil (EC 50 = 4.75 mg/L) and 12.78‐fold more potent than the parent paeonol (EC 50 = 38.99 mg/L). In vivo bioassays show that compound 6r attained 82.0% protective and 64.2% curative efficacy against Fusarium graminearum at 3.1 mg/L, outperforming chlorothalonil with corresponding efficacy values of 72.7% and 61.4%. Mechanistic studies demonstrated that compound 6r could inhibit sterol 14α‐demethylase (CYP51) activity, suppressed ergosterol biosynthesis, impaired the integrity of fungal cell membranes, and also induce intracellular reactive oxygen species accumulation. Notably, compound 6r also presented negligible phytotoxicity toward wheat seedlings and low toxicity to honeybees. CONCLUSION The results demonstrated that the ester linkage of paeonol and diphenyl ether skeletons remarkably improves antifungal activity, and compound 6r serves as a promising lead for developing novel fungicides against F. graminearum . © 2026 Society of Chemical Industry.