Design, Synthesis, and Fungicidal Activity of α-Methylene-γ-Butyrolactone Derivatives Bearing a Diphenyl Ether Moiety

The γ-butyrolactone scaffold, commonly present in natural products and bioactive compounds, has played a crucial role in the development of novel pesticides. In this study, a series of α-methylene-γ-butyrolactone derivatives containing a diphenyl ether moiety were designed and synthesized using the scaffold splicing strategy. Bioassays revealed that several target compounds demonstrated potent fungicidal activities, particularly against <i>Phytophthora capsici</i> and <i>Valsa mali</i>. Notably, compound <b>B7</b> (EC₅₀ = 0.809 mg/L) exhibited the highest antioomycete activity against <i>P. capsici</i>, outperforming <b>famoxadone</b> (EC₅₀ = 41.0 mg/L) but being less effective than <b>dimethomorph</b> (EC₅₀ = 0.180 mg/L). Meanwhile, compound <b>C22</b> (EC₅₀ = 1.47 mg/L) showed the strongest antifungal activity against <i>V. mali</i>, which was higher than those of <b>famoxadone</b> (EC₅₀ = 1.80 mg/L) and <b>dimethomorph</b> (EC₅₀ = 13.6 mg/L). <i>In vivo</i> experiments confirmed that compound <b>B7</b> has satisfactory protective and curative effects against <i>P. capsici</i>, which were better than those of <b>famoxadone</b>. Additionally, compound <b>B7</b> was found to inhibit sporangia formation, zoospore release, and cystospore germination of <i>P. capsici</i> at 10 mg/L. Physiological and biochemical studies indicated that compound <b>B7</b> can induce changes in the mycelial morphology of <i>P. capsici</i>, increase cell membrane permeability, and modulate respiratory metabolism. Furthermore, both <i>in vitro</i> enzymatic inhibition assays and molecular docking analysis suggested that the primary mechanism of action of compound <b>B7</b> may involve binding to complex III on the respiratory chain. This work provides valuable insights for the development of α-methylene-γ-butyrolactone derivatives incorporating a diphenyl ether moiety as novel agricultural fungicidal agents.