Discovery of 3,5- Bis (trifluoromethyl)phenyl-Substituted Isoxazoline Derivatives as Insecticide Candidates

Abstract Isoxazoline insecticides are effective in controlling a variety of agricultural pests; however, their high toxicity to honeybees can limit their agricultural application. In this study, we designed and synthesized a series of isoxazoline derivatives using a fluorine-distribution-guided optimization strategy. Bioassays demonstrated that several derivatives retained potent insecticidal activity. Notably, A34 exhibited potent insecticidal activity against Plutella xylostella, Spodoptera frugiperda, Spodoptera exigua and Spodoptera litura, with LC50 values of 0.05, 0.49, 0.21, and 0.29 mg/L, respectively. Importantly, A34 displayed reduced toxicity to honeybees, with an LD50 value of 2.12 μg/bee, 23.6-fold higher than that of fluralaner. SAR analyses indicated that the terminal amide architecture and fluorination pattern were associated with both insecticidal activity and acute oral toxicity to honeybees. Computational analyses suggested possible differences in receptor interactions between A34 and fluralaner. These findings provide a basis for developing isoxazoline insecticide candidates with potent insecticidal activity and reduced toxicity to honeybees.