以钙离子通道为靶标的新型绿色杀虫剂创制研究

Diamide insecticides, such as Flubendiamide, Chlorantraniliprole, which target on the insect calcium channel, also known as ryanodine receptor (RyR), have become one of hot topics of the pesticide field in recent years because of their unique mode of action, high efficacy and safety. Three commercial diamide insecticides have better control effect against a variety of agricultural pests, however, the innovation research for more new kind of insecticide candidates are urgently needed because of the development of resistance and the their limited use in some farmland. For finding and developing novel green and ecologically safe agrochemicals, this project will focus on the discovery and optimization of new lead structure and structure-activity relationship (SAR) study based on our preliminary RyR insecticides research work. (1) To rationally design and synthesize series of amide bond-modified novel compounds based on the lead structures of diamide insecticides and structural information of 3D pharmacophore model-screening obtained from our preliminary work; (2) To make structural modification of natural alkaloid caffeine of RyR activator and synthesize novel caffeine derivatives; (3) Try to carry out homology modeling for insect RyR 3D structure and molecular design based on such structure; (4) To use cell electrophysiological techniques to carry out mode of action study of the synthesized compounds with high insecticidal activities; (5) To study the SAR rule of the synthesized compounds. Through this project, it is expected to enrich the lead structure types of insecticides targeting on the calcium channel, and to discover some new lead compounds with higher insecticidal activities, as well as candidate species with application prospects. The results will be of great significance for the R & D of novel green, ecologically safe insecticides and the development of pesticide science.

作用于钙离子通道(或称RyR)的双酰胺类杀虫剂由于方式独特、超高效安全等优点，已成为杀虫剂领域的研发热点。已商品化的3个双酰胺类杀虫剂对多种农业害虫有很好的防治效果，但抗性的发展及部分农田的限制使用迫切需要创制更多新的候选品种。为寻找开发新型绿色农用化学品，本课题拟在前期工作基础上重点致力于新先导发现和结构优化以及构效关系研究：(1) 以双酰胺类杀虫剂为先导结构，结合三维药效团模型搜寻所得结构信息，设计合成多类型酰胺键改造的新衍生物；(2) 对RyR激活剂天然生物碱咖啡因结构修饰和衍生；(3) 尝试进行昆虫RyR三维结构的同源模建及分子设计工作；(4) 利用细胞电生理技术进行高活性化合物作用机制研究；(5) 研究化合物构效规律。通过研究有望丰富靶向钙离子通道杀虫剂的先导结构类型并发现更高活性的新先导，以及具开发应用前景的候选品种。研究结果对绿色生态安全杀虫剂创制和农药学科发展具有重要意义。

针对昆虫钙离子通道(RyR)靶标开发的双酰胺类杀虫剂因具有作用方式独特、超高效、选择性好、对环境生态安全等优点备受关注，但抗性的发展及部分农田的限制使用迫切需要研发更多新的候选品种。本项目针对昆虫RyR靶标，开展了以双酰胺类杀虫剂为先导结构，结合三维药效团模型搜寻所得结构信息，进行多类型酰胺键改造等方面的新衍生物设计合成和生物活性研究，对RyR激活剂天然生物碱咖啡因进行了结构修饰和衍生。通过研究工作的开展，共设计合成了各系列新化合物约计360个，经1H NMR，13C NMR，IR，元素分析，高分辨质谱以及X-射线单晶衍射等手段确证了结构，测试了新化合物杀虫及杀菌、杀螨农药生物活性，发现了含氟苯基吡唑羧酸衍生物、含N-芳基吡咯酰胺类化合物、含硫醚/砜基团的吡唑酰胺衍生物、含N-取代磺酰亚胺基的吡唑酰胺化合物、苯基吡唑硫脲类化合物、以及含噻吩基吡啶和硫基团的乙酰芳胺衍生物等高活性新的杀虫剂先导，部分化合物尤其是含氟苯基吡唑羧酸衍生物（酰胺、酰基硫脲）具有一定的应用前景。发现了含苯并噻唑氨基和杂芳基的萘酚类以及含不同氧化态三氟丁烯硫基取代的甲基黄嘌呤类（咖啡因类似物）新型杀虫/杀螨活性先导值得后续关注。还发现含N-吡啶基吡唑-β-内酰胺等多杂环类、含α-氨基磷酸酯基团的吡唑衍生物等新化合物可作为杀菌剂先导进行深入研究。利用细胞电生理测试平台并结合钙成像技术研究了高活性杀虫化合物的作用机制。利用CoMFA等研究了相应系列化合物的构效关系，获得了可用于继续优化设计的有益信息。开展了昆虫RyR三维结构同源模建、虚拟筛选以及分子对接等分子设计工作，为以RyR为靶标的新型农药研发提供了重要参考和借鉴。本项目基本按照原计划较好地完成了各项工作，取得的系列研究结果对绿色生态安全杀虫剂创制和农药学科发展具有重要意义。在项目资助下共发表SCI收录文章18篇；申请中国发明专利4项；培养博士生3人，硕士生4人。