摘要/Abstract

近年来, 越来越多的新烟碱类杀虫剂由于对蜜蜂存在的安全问题陆续被欧盟和美国禁用. 本研究通过虚拟筛选结合生物活性评价的双重策略实现骨架跃迁, 发现苯乙酰腙类化合物VS-04对大豆蚜表现出较好的杀虫活性, 且化合物VS-04和蜜蜂烟碱型乙酰胆碱受体(nAChRs)的作用模式与传统的吡虫啉显著不同. 新合成的苯乙酰腙类似物3c和3e在500 μg/mL浓度下对大豆蚜致死率为70%, 具有中等活性. 更重要的是, 通过蜜蜂毒性研究确证化合物3c和3e对蜜蜂表现出极低的急性接触毒性, 其LD₅₀值(30.35和124.4 μg/bee)比吡虫啉(0.019 μg/bee)低3~4个数量级. 通过化合物3m晶体结构确证化合物3c的酰腙结构以L型低能构象指向蜜蜂受体α亚基, 进一步预示其低蜂毒特征. 基于化合物3e进一步优化得到的化合物4f和4g对大豆蚜表现出更好的致死活性, 其LC₅₀值分别是83.42和66.44 μg/mL, 优于化合物3e (LC₅₀=147.30 μg/mL). 这一研究将有利于以不同昆虫nAChR结构为靶标发现环境友好的新烟碱替代物.
关键词: 新烟碱, Aplysia californiaacetylcholine binding protein (Ac-AChBP), 骨架跃迁, 苯乙酰腙化合物, 靶标和非靶标选择性
Increasing numbers of neonicotinoids have recently been banned by the European Union (EU) and the United States of America (USA) due to their potential high risk to pollinating bees. In this work, a phenylacetohydrazone compound VS-04 was found via scaffold hopping to exert good mortality rate against soybean aphids based on a double combinational strategy of virtual screening and bioassay technique. The molecular interaction mode to honeybee nicotinic acetylcholine receptor (nAChR) for the newly found compound VS-04obviously differed from that of the known imidacloprid. The newly synthesized phenylacetohydrazone compounds 3c and 3e caused soybean aphids to have a moderate mortality rate of approximately 70% at a concentration of 500 μg/mL. Importantly, the bee-toxicity study confirmed that compounds 3c and 3e showed much lower acute contact toxicity with LD₅₀ value (30.35 and 124.4 μg/bee) of 3~4 orders of magnitude than that of imidacloprid (0.019 μg/bee). The hydrazone substructure of compound 3c was found to be aL-shape low-energy conformation confirmed by a crystal structure of its analog 3m and inversely point towardα subunit of honeybee receptor via a molecular interaction study, indicating its potential low bee-toxicity. Compounds 4fand 4g (optimized derivatives of 3e) indeed showed better insecticidal activity against soybean aphids with moderate LC₅₀ values of 83.42 and 66.44 μg/mL, respectively, compared with 3e (147.30 μg/mL). This work facilitates the discovery of suitable and ecofriendly candidates as alternatives to neonicotinoids based on different insect nAChR structure.
Key words: neonicotinoid, Aplysia californiaacetylcholine binding protein (Ac-AChBP), scaffold hopping, phenylacetohydrazone compounds, target and nontarget selectivity


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