以酪氨酸酶靶标为导向的新型农用杀菌剂创制研究

为了发现新作用机制的农用杀菌剂，本项目在前期研究工作基础之上，拟以真菌酪氨酸酶为靶标，开展以酪氨酸酶靶标为导向的新型农用杀菌剂创制研究。内容主要包括三个方面：1）以前期发现的高活性肉桂醛缩氨基硫脲类化合物IIIB-02为先导，系统开展结构优化研究，通过设计合成、以及不同水平活性测试和筛选研究，以期发现1-2个具有开发应用前景的杀菌剂候选化合物；2）以Agaricus bisporus酪氨酸酶的晶体结构为基础，利用分子动力学、分子对接技术，研究活性化合物与酪氨酸酶受体的相互作用规律，分析和解释配体化合物与受体结合的关键位点，探讨小分子与受体的作用机理，为进一步设计、发现具有更高活性的酪氨酸酶抑制剂提供理论指导；3）针对发现的高活性化合物，进行杀菌谱筛选、温室和田间小区试验、以及适用作物和I期毒性试验研究，为产业化开发提供决策依据。本项目将对提升基于酪氨酸酶靶标的新农药创制研究工作具有重要意义

In order to find novel pesticide with new target, this project will focus on the discovery of new fungicides as tyrosinase inhibitors. Based on our preliminary results, the story contains three parts as follows: 1）The optimization of lead compound: cinnamic aldehyde thiosemicarbazone with high activity, discovered in our former work, will be structurally optimized with the method of pesticide molecular design. The designed compounds will be synthesized and evaluated via in vitro and in vivo fungicidal bioassay with the purpose of finding 1-2 new promising candidates as fungicides for further development; 2）The study on the interaction between active compounds and tyrosinase: the Crystal structure of Agaricus bisporus tyrosinase is basically chosen for the interaction study with different active compounds. The key binding sites and interaction mechanism will be investigated by molecular docking and molecular dynamics. The results will be useful for further design of new tyrosinase inhibitors with higher activity; 3）The intensive study on active compound: To provide decision-making basis for industrial development, the fungicidal spectrum, activity in greenhouse and in field trial, as well as its safety to crops and oral/skin cute toxicity to rat, will be carried out for the candidate active compound. The above work will be of great significance to enhance the research of the new pesticide discovery targeted tyrosinase.