三唑酰肼类化合物NAU-6ad抑制禾谷镰刀菌的作用靶标及结构优化研究

禾谷镰刀菌引起的小麦赤霉病严重危害我国小麦安全生产，但目前可用于小麦赤霉病防治的药剂有限，急需研发高效、低风险的新型杀菌剂。申请人前期研究发现1,2,3-三唑酰肼类化合物NAU-6ad对小麦赤霉病具有良好的田间防效，但其作用靶标尚不明确，进一步开发受限。本项目拟以活性分子NAU-6ad为探针，运用基于活性的蛋白质谱分析、转录组/蛋白质组联合分析技术探究化合物的作用靶标；通过蛋白同源表达-亲和力/活性测定、同源建模-分子对接方法进行靶标验证；基于骨架跃迁策略设计NAU-6ad类似物分子，并利用虚拟筛选模型明确优势骨架，开展基于骨架多样性和取代基多样性的衍生合成；测试化合物对病原菌和靶标的活性，并在3D-QSAR分析基础上，进一步开展结构优化；通过评价高活性化合物的杀菌活性和作物安全性，发现作用机制新颖、活性显著的杀菌剂候选化合物。本项目的研究结果对促进我国新型杀菌剂创制研究具有重要意义。

Fusarium head blight (FHB), caused by Fusarium graminearum, is one of the most serious and hazardous diseases of wheat in China. However, very few fungicides could be used for controlling FHB till now. There is still an urgent need to develop new fungicides with high-efficiency and low-risk properties. Our previous work has found that NAU-6ad, a novel 1,2,3-triazole hydrazide compound, has significant control effect on FHB. But the further development of NAU-6ad is restricted because its target is unclear. Therefore, this project intends to explore the target of NAU-6ad and optimize the chemical structure to discover new fungicide candidates. Firstly, using NAU-6ad as a probe, the activity-based protein profiling (ABPP) and transcriptome/proteome combined analysis will be applied for target screening. Secondly, the candidate targets will be validated by protein homologous expression and affinity/activity assay, as well as homology modeling and molecular docking simulation. Thirdly, the scaffolds diversity and substituents diversity oriented strategies will be applied for the synthesis of NAU-6ad analogs based on scaffold hopping molecular design method and receptor based virtual screening. After testing the inhibitory activities against phytopathogens and molecular target, the chemical structure will be further optimized based on 3D-QSAR analysis. Finally, through intensive bioactivity and crop safety evaluation, new fungicide candidates with novel mode of action and significant fungicidal activity will be obtained. The results of this project will be of great significance for the research and development of novel fungicides in China.