Design, Synthesis,\nand Fungicidal Activity of α‑Methylene-γ-Butyrolactone\nDerivatives Bearing a Diphenyl Ether Moiety

The γ-butyrolactone scaffold, commonly present\nin natural\nproducts and bioactive compounds, has played a crucial role in the\ndevelopment of novel pesticides. In this study, a series of α-methylene-γ-butyrolactone\nderivatives containing a diphenyl ether moiety were designed and synthesized\nusing the scaffold splicing strategy. Bioassays revealed that several\ntarget compounds demonstrated potent fungicidal activities, particularly\nagainst Phytophthora capsici and Valsa mali. Notably, compound <b>B7</b> (EC<sub>50</sub> = 0.809 mg/L) exhibited the highest antioomycete activity\nagainst P. capsici, outperforming <b>famoxadone</b> (EC<sub>50</sub> = 41.0 mg/L) but being less effective\nthan <b>dimethomorph</b> (EC<sub>50</sub> = 0.180 mg/L). Meanwhile,\ncompound <b>C22</b> (EC<sub>50</sub> = 1.47 mg/L) showed the\nstrongest antifungal activity against V. mali, which was higher than those of <b>famoxadone</b> (EC<sub>50</sub> = 1.80 mg/L) and <b>dimethomorph</b> (EC<sub>50</sub> = 13.6 mg/L). <i>In vivo</i> experiments confirmed that\ncompound <b>B7</b> has satisfactory protective and curative\neffects against P. capsici, which were\nbetter than those of <b>famoxadone</b>. Additionally, compound <b>B7</b> was found to inhibit sporangia formation, zoospore release,\nand cystospore germination of P. capsici at 10 mg/L. Physiological and biochemical studies indicated that\ncompound <b>B7</b> can induce changes in the mycelial morphology\nof P. capsici, increase cell membrane\npermeability, and modulate respiratory metabolism. Furthermore, both <i>in vitro</i> enzymatic inhibition assays and molecular docking\nanalysis suggested that the primary mechanism of action of compound <b>B7</b> may involve binding to complex III on the respiratory chain.\nThis work provides valuable insights for the development of α-methylene-γ-butyrolactone\nderivatives incorporating a diphenyl ether moiety as novel agricultural\nfungicidal agents.