Discovery of new N-Phenylamide Isoxazoline derivatives with high insecticidal activity and reduced honeybee toxicity

Abstract

Isoxazoline is a novel structure with strong potential for controlling agricultural insect pests, but its high toxicity to honeybees limits its development in agriculture. Herein, a series of N-phenylamide isoxazoline derivatives with low honeybee toxicity were designed and synthesized using the intermediate derivatization method. Bioassay results showed that these compounds exhibited good insecticidal activity. Compounds 3b and 3f showed significant insecticidal effects against Plutella xylostella (P. xylostella) with median lethal concentrations (LC₅₀) of 0.06 and 0.07 mg/L, respectively, comparable to that of fluralaner (LC₅₀ = 0.02 mg/L) and exceeding that of commercial insecticide fluxametamide (LC₅₀ = 0.52 mg/L). It is noteworthy that the acute honeybee toxicities of compounds 3b and 3f (LD₅₀ = 1.43 and 1.63 μg/adult, respectively) were significantly reduced to 1/10 of that of fluralaner (LD₅₀ = 0.14 μg/adult), and were adequate or lower than that of fluxametamide (LD₅₀ = 1.14 μg/adult). Theoretical simulation using molecular docking indicates that compound 3b has similar binding modes with fluralaner and a similar optimal docking pose with fluxametamide when binding to the GABA receptor, which may contribute to its potent insecticidal activity and relatively low toxicity to honey bees. This study provides compounds 3b and 3f as potential new insecticide candidates and provides insights into the development of new isoxazoline insecticides exhibiting both high efficacy and environmental safety.

Keywords: Honeybee toxicity; Insecticidal activity; Isoxazolines; N-phenylamides.