含取代苯肼的tetramic acid先导物的结构优化、杀菌活性及3D-QSAR研究

本项目拟对具有原始创新的先导物进行结构优化，筛选能有效防治作物真菌病害的新型绿色杀菌剂。经对天然产物tenuazonic acid进行结构修饰，发现含取代苯肼的吡咯烷二酮化合物对小麦赤霉病菌等植物病原菌具有显著的抑制活性，且与多菌灵无交互抗性。拟在生物电子等排原理和类同合成法指导下，对二次先导物进行优化设计，重点对肼基的2位氮原子和吡咯环进行修饰，合成含取代苯肼、取代苯基酰肼、取代苯基酰胺和取代苯胺基团的二卤代吡唑及氟代甲基吡唑类衍生物，提高先导物的杀菌活性与结构稳定性。同时，通过3D-QSAR构效关系分析，建立CoMFA和CoMSIA模拟分子作用模型，对目标分子结构进行再优化，并对其中优异者进行急性毒性与田间小区药效试验，力争筛选到1-2个具有自主知识产权的高效、低毒、环境相容性好的候选化合物。本项目设计的化合物分子骨架新颖，作为杀菌剂创制是一有益尝试，可为作物病害防治提供新的有效手段。

This research subject intends to optimize the molecular structures of leading compounds tetramic acids incorporating the moiety of substituted phenylhydrazines, which embodies the original innovation, for screening novel green fungicides which can effectively prevent the fungal diseases of crops. The microbial metabolite tenuazonic acid has a variety of biological activities, by modifying its structure, the derivatives pyrrolidinediones containing substituted phenylhydrazine were found having significant inhibitory activity against wheat scab (Fusarium gramineaum) and other plant pathogens, and no cross resistance to carbendazim. The secondary leading compound was planed to be optimized under the guidance of the bioisostere principle and the similar synthesis method. These modifying would be focused on 2-nitrogen atom of hydrazine group and the pyrrole ring. Two-halogenated pyrazole or fluorinated methyl pyrazole derivatives which containing substituted phenylhydrazine, phenyl acylhydrazide, phenyl amide and phenyl amine moiety would be designed and synthesized for improving the fungicidal activity and heightening the structure stability. Moreover, through the fungicidal activity screening and analysis of 3D-QSAR, the CoMFA and CoMSIA model would be established to simulate the molecular interaction, the target molecules would be further optimized, and the excellent compounds would be carried out the field efficacy and acute toxicity test. We expect to obtain one or two new candidate compounds possessing independent intellectual property rights and good properties of high efficiency, low toxicity and good environmental compatibility, which could be recommended to enter the development stage of candidate pesticides. The designed novel molecular scaffolds using as new fungicides to research and develop is a useful attempt, could provide new and effective control techniques against plant diseases.