Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China.
Jilin Provincial Key Laboratory of Animal Resource Conservation and Utilization, Northeast Normal University, Changchun, Jilin 116000, People's Republic of China.
J Agric Food Chem. 2024 Jun 12;72(23):12956-12966. doi: 10.1021/acs.jafc.4c00679. Epub 2024 May 31.
Bees, one of the most vital pollinators in the ecosystem and agriculture, are currently threatened by neonicotinoids. To explore the molecular mechanisms of neonicotinoid toxicity to bees, the different binding modes of imidacloprid, thiacloprid, and flupyradifurone with nicotinic acetylcholine receptor (nAChR) α1β1 and cytochrome P450 9Q3 (CYP9Q3) were studied using homology modeling and molecular dynamics simulations. These mechanisms provided a basis for the design of compounds with a potential low bee toxicity. Consequently, we designed and synthesized a series of triazinone derivatives and assessed their bioassays. Among them, compound not only displayed substantially insecticidal activities against (LC = 4.40 mg/L) and (LC = 6.44 mg/L) but also had low toxicity to . Two-electrode voltage clamp recordings further confirmed that compound interacted with the nAChR α1 subunit but not with the nAChR α1 subunit. This work provides a paradigm for applying molecular toxic mechanisms to the design of compounds with low bee toxicity, thereby aiding the future rational design of eco-friendly nicotinic insecticides.
蜜蜂是生态系统和农业中最重要的传粉媒介之一，目前正受到新烟碱类杀虫剂的威胁。为了探究新烟碱类杀虫剂对蜜蜂的毒性的分子机制，我们使用同源建模和分子动力学模拟研究了吡虫啉、噻虫啉和氟吡呋喃酮与烟碱型乙酰胆碱受体（nAChR）α1β1和细胞色素 P450 9Q3（CYP9Q3）的不同结合模式。这些机制为设计潜在低毒性的化合物提供了依据。因此，我们设计并合成了一系列三嗪酮衍生物，并评估了它们的生物活性。其中，化合物 不仅对 （LC = 4.40 mg/L）和 （LC = 6.44 mg/L）具有显著的杀虫活性，而且对 毒性较低。双电极电压钳记录进一步证实，化合物 与 nAChR α1 亚基相互作用，而不是与 nAChR α1 亚基相互作用。这项工作为将分子毒性机制应用于设计低毒性化合物提供了范例，从而有助于未来环保型烟碱类杀虫剂的合理设计。
