Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China; Key Laboratory of National Forestry and Grassland Administration on Pest Chemical Control, Beijing 100193, People's Republic of China.
Jilin Provincial Key Laboratory of Animal Resource Conservation and Utilization, Northeast Normal University, Changchun, Jilin 116000, People's Republic of China; Key Laboratory of Vegetation Ecology, MOE, Northeast Normal University, Changchun, Jilin 116000, People's Republic of China.
Int J Biol Macromol. 2023 Dec 31;253(Pt 2):126719. doi: 10.1016/j.ijbiomac.2023.126719. Epub 2023 Sep 9.
Nicotinic acetylcholine receptor (nAChR) is recognized as a significant insecticide target for neonicotinoids and some agonists. In this study, the nAChR α1 subunit from Apis mellifera was first found to be narrowly tuned to different bee toxicity insecticides, namely, sulfoxaflor (SFX) and flupyradifurone (FPF). Hence, novel sulfoximine derivatives 7a-h were rationally designed and synthesized by introducing a benzo[d][1,3]dioxole moiety into a unique sulfoximine skeleton based on the binding cavity characteristics of Amelα1/ratβ2. The two electrode voltage clamp responses of 7a-h were obviously lower than that of SFX, indicating their potentially low bee toxicity. Besides, representative compounds 7b and 7g exhibited low bee toxicity (LD > 11.0 μg/bee at 48 h) revealed by acute contact toxicity bioassays. Molecular modelling results indicated that Ile152, Ala151, and Val160 from honeybee subunit Amelα1 and Lys144 and Trp80 from aphid subunit Mpα1 may be crucial for bee toxicity and aphicidal activity, respectively. These results clarify the toxic mechanism of agonist insecticides on nontargeted pollinators and reveal novel scaffold sulfoximine aphicidal candidates with low bee toxicity. These results will provide a new perspective on the rational design and highly effective development of novel eco-friendly insecticides based on the structure of the nAChR subunit.
烟碱型乙酰胆碱受体 (nAChR) 被认为是新烟碱类和一些激动剂等杀虫剂的重要靶标。本研究首次发现，蜜蜂 nAChRα1 亚基对不同的蜜蜂毒性杀虫剂，即磺酰氟 (SFX) 和氟吡呋喃酮 (FPF)，具有较窄的选择性。因此，根据 Amelα1/ratβ2 的结合腔特征，我们合理设计并合成了一系列新型磺肟衍生物 7a-h，通过在独特的磺肟骨架中引入苯并[d][1,3]二恶唑部分。7a-h 的双电极电压钳响应明显低于 SFX，表明它们可能具有较低的蜜蜂毒性。此外，代表性化合物 7b 和 7g 通过急性接触毒性生物测定显示出较低的蜜蜂毒性 (48 h 时 LD>11.0μg/bee)。分子模拟结果表明，来自蜜蜂亚基 Amelα1 的 Ile152、Ala151 和 Val160 以及来自蚜虫亚基 Mpα1 的 Lys144 和 Trp80 可能对蜜蜂毒性和杀蚜虫活性至关重要。这些结果阐明了激动剂杀虫剂对非靶标传粉者的毒性机制，并揭示了具有低蜜蜂毒性的新型磺肟杀蚜虫候选物。这些结果将为基于 nAChR 亚基结构的新型环保杀虫剂的合理设计和高效开发提供新的视角。
