Innovative Research on the Agricultural Insecticidal Activity of Lotilaner and Its Derivatives

Abstract Isoxazolines exhibit potent insecticidal activity, but their toxicity to beneficial insects limits agricultural applications. Here, we first explored the veterinary isoxazoline lotilaner as a lead for agricultural insecticide discovery. We designed and synthesized a series of diacylhydrazine-containing derivatives. Lotilaner showed strong activity against P. xylostella (LC50 = 0.305 mg/L), while I-9S exhibited activity against S. frugiperda (LC50 = 2.69 mg/L) comparable to that of lotilaner (3.41 mg/L). I-9S also outperformed its enantiomer I-9R, indicating stereoselective insecticidal activity. Molecular docking, molecular dynamics simulations, and DFT calculations provided insights into potential receptor interactions and electronic properties. Notably, the honeybee acute oral LD50 increased from 0.297 μg/bee for lotilaner to 3.32 μg/bee for I-9S, representing an approximately 11-fold increase in LD50 and reduced honeybee toxicity. These findings support scaffold modification of lotilaner as a promising approach to developing agricultural isoxazoline insecticides with favorable activity and improved honeybee safety.