具有双作用位点靶向磺酰脲受体的新型昆虫生长调节剂的设计合成与生物活性研究

The molecular target-oriented design of pesticide molecules is an important development direction of the new pesticide innovation today. Based on the significant discovery that diflubenzuron and glibenclamide act on the same target site on the sulfonylurea receptor protein in tested insects, novel insect growth regulators targeting sulfonylurea receptor with two binding sites will be designed and synthesized for the first time, and the isotope labeling method will be used to study the correlation between in-vitro activity and in-vivo insecticidal activity. The crucial involvement of two structural units of target compounds in the insectical activity will be varified and the molecular target site and action mechanism will be preliminarily clarified, meanwhile, a new method which is used to design and find novel insect growth regulators based on the sulfonylurea receptor will be established. Furthormore, the gradually in-depth structural optimization of target molecules, which showed a high binding affinity to the action site on sulfonylurea receptor protein, will be expected to find one highly effective and low-toxic pesticide candidate targeting sulfonylurea receptor and one lead compound of type-specific pesticides. This project will provide important theoretical guidance for pesticide innovation based on the target receptor protein and find a new way to dramatically increase the insecticidal activity level of benzoylurea insecticides.

分子靶标导向的农药分子设计是当前新农药创制的重要发展方向。本项目基于除虫脲和格列本脲对受试昆虫具有共同的作用靶标-磺酰脲受体蛋白这一重大发现，拟设计合成具有双作用位点靶向磺酰脲受体的新型昆虫生长调节剂，运用同位素标记法研究其离体活性与活体杀虫活性之间的关系，验证双作用位点分子结构片段在发挥杀虫活性中的关键作用，建立一种以磺酰脲受体为靶标设计和筛选具有新颖结构昆虫生长调节剂的新方法，并初步阐明高活性新型昆虫生长调节剂的分子作用靶点及其作用机制。同时，通过离体活性与活体杀虫活性结果的不断相互验证，逐步深入地优化与磺酰脲受体蛋白结合能力强的目标化合物的分子结构，有望发现1个高效低毒、靶向磺酰脲受体的农药候选品种和特异性绿色农药先导结构。本项目研究将为基于靶标受体的新农药的创制提供重要的理论指导，为大幅度提高苯甲酰脲类杀虫剂的活性水平提供一条崭新的研究途径。

分子靶标导向的农药分子设计是当前新农药创制的重要发展方向。本项目基于除虫脲和格列本脲对受试昆虫具有共同的作用靶标-磺酰脲受体蛋白这一重大发现，设计合成了5类65个具有双作用位点靶向磺酰脲受体的新型昆虫生长调节剂，所有化合物的结构均经1H NMR、13C NMR及HRMS确认。在探索合成这些化合物的过程中，建立一种高效构筑1-(2-吡啶基)-1,2,3-三唑类化合物的新方法。在对化合物进行生物活性筛选的过程中，发现了2个结构新颖、具有广谱杀真菌活性的农药先导化合物。