Rational Design and Synthesis of Isoxazoline Derivatives with Low Bee-Toxicity Based on Bee GABA Receptors.

The isoxazoline insecticide, such as fluralaner, exhibits strong insecticidal activity against pests while showing no cross-resistance. However, due to its toxicity to bees, the use of Fluralaner is restricted in veterinary antiparasitic applications. Hence, how to modify the structure of fluralaner to maintain the insecticidal activity and reduce the toxicity to bees is vital and meaningful. In this study, a virtual screening of 11 diamide substructures was conducted based on the GABA receptor of bees (), and four compounds with lower docking scores were regarded as potential low bee toxicity compounds. Among them, compound containing a thiophene diamine motif was used as a lead compound. Subsequently, compounds - and - were synthesized based on compound . Interestingly, compound exhibited LC values of 1.4 μg/mL against the diamondback moth (), outperforming the commercial insecticide ethiprole (LC = 2.9 μg/mL). Furthermore, compound exhibited LC values of 9.9 μg/mL against fall armyworm (), also outperforming the commercial insecticide Fipronil (LC = 78.8 μg/mL). Compound exhibited LC values of 12.4 μg/mL against the corn borer (), which surpassed that of the commercial insecticide ethiprole (30.8 μg/mL). Although the insecticidal activity of compound against and was not as potent as Fluralaner, its toxicity to bees was only 1/200 that of Fluralaner. Molecular dynamics studies elucidated the interaction mode of with the GABA receptor of the bee. has the potential to serve as a candidate isoxazoline insecticide and a low-toxicity alternative to Fluralaner, offering valuable insights for the future design of isoxazoline insecticide.