Rational Design of Novel GABA Receptor Inhibitors as Potential Insecticides against Plutella xylostella and Ostrinia furnacalis

Pesticide overuse has prompted widespread insecticide resistance. Isoxazolines represent a promising scaffold, featuring safety and efficacy without having any cross-resistance. Previously, we identified the derivative L17 with moderate activity against Plutella xylostella . Based on its binding mode with the GABA receptor, 30 novel derivatives were designed and synthesized. Subsequent three-dimensional quantitative structure–activity relationship (3D-QSAR) optimization yielded H31, which showed enhanced insecticidal activity (LC 50 = 0.751 mg/L against P. xylostella and 0.581 mg/L against Ostrinia furnacalis ), outperforming fluxametamide. H31 also showed good activity against Spodoptera frugiperda (LC 50 = 2.35 mg/L). Potted experiments validated its control efficacy. Enzyme-linked immunosorbent assay (ELISA) confirmed the GABA receptor as the target, while density functional theory (DFT) computations and molecular docking demonstrated that the diamide moiety provides more hydrogen and halogen bond interactions with the GABA receptor, consistent with improved potency. Notably, H31 showed safety toward bumblebees, zebrafish, and mouse liver cells. This work provides insights for developing the next-generation insecticides.