Design, Synthesis, and Insecticidal Potential of 1,2,4-Oxadiazole-Fused Isoxazoline Derivatives as GABA Receptor Antagonists

To address the escalating pesticide resistance in lepidopteran pests, a 1,2,4-oxadiazole motif was integrated into an isoxazoline scaffold to synthesize 25 novel derivatives. Compound H10 exhibited exceptional insecticidal activity against Plutella xylostella (LC₅₀ = 0.21 mg/L), significantly outperforming both fluxametamide (LC₅₀ = 1.36 mg/L) and ethiprole (LC₅₀ = 11.2 mg/L). Furthermore, H10 demonstrated 36-fold greater efficacy against Spodoptera frugiperda than ethiprole. Mechanistic investigations utilizing two-electrode voltage-clamp electrophysiology revealed that H10 functions as a potent antagonist of the RDL1 GABA Receptor, effectively suppressing GABA-evoked currents. Molecular docking and molecular dynamics simulation indicated that H10 binds deeply within the receptor pore, establishing stable interactions with critical residues (e.g., Ala302 and Phe206) to disrupt channel gating. This study presents a successful structural optimization strategy for isoxazoline insecticides and highlights H10 as a promising candidate for next-generation pest management.