Structural Modification of Bifenox Derivatives: Discovery of Novel Diaryl Thioethers as Potent Insect Trehalase Inhibitors

To discover novel noncarbohydrate trehalase inhibitors, 62 bifenox derivatives were designed and synthesized in this study. Among them, diaryl thioether 2b-1 exhibited optimal trehalase inhibitory activity with 72.5% inhibition rate at 100 μM and a Ki value of 36.3 μM, superior to bifenox (56.5 μM). Insecticidal activity assay showed that compound 2b-1 displayed stronger insecticidal potency against Ostrinia furnacalis (LC50 = 34.7 mg/L) than bifenox (LC50 = 61.2 mg/L). Molecular docking and density functional theory (DFT) calculations proved 2b-1 formed abundant hydrogen bonds and π-sulfur interaction with key residues of OfTreh, accompanied by a lower energy gap and enhanced electrostatic potential distribution at the active sites. Transcriptomics further verified that 2b-1 disrupted energy metabolism, activated detoxification pathways, and interfered with cuticle remodeling of Ostrinia furnacalis larvae. Collectively, this work indicated that diaryl thioether 2b-1 could serve as a promising lead for developing novel trehalase-targeting insecticides.