Yang Jianrong, Tu Hong, Tian Bihong, Zhao Zhichao, Wang Ya, Yang Zhaokai, Wu Jian
State Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Huaxi District, Guiyang 550025, China.
J Agric Food Chem. 2025 Apr 23;73(16):9489-9498. doi: 10.1021/acs.jafc.4c08476. Epub 2025 Apr 13.
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.
异恶唑啉类杀虫剂，如氟虫腈，对害虫表现出很强的杀虫活性，且无交叉抗性。然而，由于其对蜜蜂有毒性，氟虫腈在兽医抗寄生虫应用中的使用受到限制。因此，如何修饰氟虫腈的结构以保持杀虫活性并降低对蜜蜂的毒性至关重要且具有意义。在本研究中，基于蜜蜂的γ-氨基丁酸（GABA）受体对11种双酰胺亚结构进行了虚拟筛选，四种对接分数较低的化合物被视为潜在的低蜜蜂毒性化合物。其中，含有噻吩二胺基序的化合物被用作先导化合物。随后，基于化合物合成了化合物-和-。有趣的是，化合物对小菜蛾的LC值为1.4μg/mL，优于市售杀虫剂乙虫腈（LC = 2.9μg/mL）。此外，化合物对草地贪夜蛾的LC值为9.9μg/mL，也优于市售杀虫剂氟虫腈（LC = 78.8μg/mL）。化合物对玉米螟的LC值为12.4μg/mL，超过了市售杀虫剂乙虫腈（30.8μg/mL）。虽然化合物对和的杀虫活性不如氟虫腈，但其对蜜蜂的毒性仅为氟虫腈的1/200。分子动力学研究阐明了与蜜蜂GABA受体的相互作用模式。有潜力作为一种候选异恶唑啉类杀虫剂以及氟虫腈的低毒替代品，为异恶唑啉类杀虫剂的未来设计提供了有价值的见解。
