具有低抗性风险的新型线粒体复合体III抑制剂的设计、合成及杀菌活性研究

Strobilurins类杀菌剂的发现在杀菌剂发展史上具有里程碑意义，其作用靶标是线粒体复合体III。但其抗性发展速度之快却是始料未及的。因此，如何规避抗药性是针对复合体III设计合成新型杀菌剂必须面对的一项挑战。本项目拟采用膜蛋白分子动力学方法，构建出抗药性最严重的G143A突变型复合体III的三维结构，揭示其产生抗药性的分子机制。随后，以具有新颖药效团的天然产物Neopeltolide为先导，引入具有新颖作用机制的Ametoctradin的结构片段，设计具有全新骨架的目标分子，采用药效团链接碎片虚拟筛选方法对其进行结构优化，选择对野生型和G143A突变型复合体III具有较高预测活性的苗头化合物开展合成及生物活性研究，力争通过分子设计、合成及生物活性测试的研究循环，最终获得找到1-2个结构新颖、高活性、低抗性风险的先导化合物。本项目的实施将为推动我国新农药创制基础研究做出积极贡献。

The Strobilurins fungicides have created a milestone in the history of fungicide, which targeted to mitochondria complex III. However, the rate of resistance about Strobilurins fungicides was very fast and beyond our imagination. Therefore, how to avoid the resistance is a challenge to design and synthesis novel complex III fungicide. In this project, the 3D structure of G143A complex III, a serious mutation in complex III, would be built using membrane dynamics and the resistance mechanism would be studied for G143A mutation. Based on the structure of neopeltolide and ametoctradin, the novel inhibitor was designed and synthetized using pharmacophore-linked fragment virtual screening method both for wild type and G143A complex III. We strived to obtain 1-2 lead compounds with high activity and low resistance risk. We would lad the foundation for the development of new pesticide.