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 (Apis mellifera), and four compounds with lower docking scores were regarded as potential low bee toxicity compounds. Among them, compound Y11 containing a thiophene diamine motif was used as a lead compound. Subsequently, compounds A1-A16 and B1-B11 were synthesized based on compound Y11. Interestingly, compound A13 exhibited LC₅₀ values of 1.4 μg/mL against the diamondback moth (Plutella xylostella), outperforming the commercial Insecticide ethiprole (LC₅₀ = 2.9 μg/mL). Furthermore, compound A13 exhibited LC₅₀ values of 9.9 μg/mL against fall armyworm (Spodoptera frugiperda), also outperforming the commercial Insecticide Fipronil (LC₅₀ = 78.8 μg/mL). Compound B1 exhibited LC₅₀ values of 12.4 μg/mL against the corn borer (Pyrausta nubilalis), which surpassed that of the commercial Insecticide ethiprole (30.8 μg/mL). Although the insecticidal activity of compound A13 against P. xylostella and S. frugiperda 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 A13 with the GABA Receptor of the bee. A13 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.

bee toxicity; isoxazoline insecticide; molecular dynamics; thiophene diamine.