Zhang_2026_Pestic.Biochem.Physiol_219_107017

Crop pests are major biotic threats to agriculture and posing continuous challenges to global food security. Natural products provide valuable templates for pesticide discovery, and rational structural modification can enhance their potency, stability, and safety. In this study, a series of eugenol derivatives were synthesized and evaluated for insecticidal activity. Compound 3r showed remarkable toxicity against S. frugiperda (the LD(50) value of contact toxicity and stomach toxicity were 0.079 mg /larva and 0.501 mg/mL, respectively.), 6.0-fold and 4.4-fold stronger than eugenol, and exhibited 41.8-fold higher cytotoxicity toward Sf9 cells (IC(50) = 0.011 mg/mL vs. 0.46 mg/mL). Compound 3g displayed potent activity against O. surinamensis (LD(50) = 5.25 x 10(-4) mg/adult), 5.2-fold greater than eugenol, while both 3g and 3r showed low toxicity to honeybees. Molecular docking and dynamics simulations revealed that 3r formed stable interactions with acetylcholinesterase (AChE), consistent with enhanced enzymatic activity. Structure-activity analysis indicated that introducing a flexible alkoxy chain bearing a trifluoromethyl group at the phenolic hydroxyl significantly improved insecticidal potency. Overall, 3r and 3g represent promising leads for developing next-generation, plant-derived insecticides with high efficacy and ecological safety.