含单萜酚结构的多靶点杂合分子设计、合成及抑菌活性研究

Combining natural products with special physiological mechanism with fungicides to design and synthesize novel, highly active multi-target hybrid molecules, which is an effective approach to develop the novel, active ingredients of fungicides from natural products. How to reasonably combine two active fragments to one molecule is a difficult point in hybrid molecules design. In our previous studies, a series of phenolic monoterpenes (PMs) esters with heteroaromatic carboxylic acids were designed by combining the PMs molecules with the common heterocyclic groups of succinate dehydrogenase inhibitors (SDHIs). Based on the previous research, the project will proceed with the following studies: Firstly, the “PMs-SDHIs” hybrid molecules will be designed by combining the PMs molecules with the molecules or pharmacophore of SDHIs via the molecular docking and virtual screening methods of the computer-aided drug design (CADD). Secondly, the hybrid molecules and their derivatives with different bioisosteric groups will be synthesized, and the antifungal activities and succinate dehydrogenase inhibitory activity of the synthesized compounds will be evaluated to screen the highly active hybrid molecules with multi-targets. At last, the in vivo antifungal activity and systematic property will be determined to evaluate the potential use of hybrid molecules as active ingredients of fungicides. The implementation of this project is expected to discover a new type of multi-target fungicide that integrate the advantages of systemic and protectant fungicides and natural products.

将抑菌机制独特的天然产物与现有杀菌剂分子“拼合”，设计、合成结构新颖、高活性的多靶点杂合分子，是利用天然产物研发新型杀菌剂活性成分的有效途径。如何将两个活性片段合理拼合是多靶点杂合分子设计的难点。项目申请人在前期工作中将单萜酚类化合物（PMs）与琥珀酸脱氢酶抑制剂类杀菌剂（SDHIs）中常见基团“拼合”，获得了一系列“单萜酚-杂环甲酸脂”类多靶点杂合分子。本项目拟在前期研究基础上，利用计算机辅助药物设计中分子对接、虚拟筛选等方法辅助PMs与SDHIs分子或其药效团“拼合”，合理设计“PMs-SDHIs”杂合分子；合成杂合分子并根据“生物电子等排”原理合成其衍生物，测定其抑菌活性和SDH抑制活性，筛选高活性、多靶点杂合分子；研究杂合分子的内吸传导性并通过活体实验评价其作为杀菌剂有效成分的潜力。通过本项目的实施，有望创制出集内吸性和保护性杀菌剂及天然产物优势于一体的多靶点新型杀菌剂。

植物病害的发生流行严重制约着农业生产发展、威胁着农产品质量安全。化学农药作为植物病害防治的重要手段，在植物保护中占主导地位。但多数化学农药作用位点单一，产生抗性风险高。因此，亟需研发高效、低毒、多靶点、低抗性风险的新型杀菌剂。为获得具有高活性、多靶点的活性成分，本研究从天然单萜酚类化合物和琥珀酸脱氢酶抑制剂类杀菌剂出发，一方面将单萜酚与SDHI分子及其药效团拼合，设计单药多靶点杂合分子，结合计算机辅助手段设计、合成了112个杂合分子，其中酯类、醚类、酰胺类化合物（80个）结构稳定，32个酰脲类化合物结构不稳定。通过对80个化合物进行抑菌活性筛选，获得了2个活性理想、与SDHIs无交互抗性、具有潜在多靶点效应的杀菌剂活性成分。另一方面将天然单萜酚和SDHI类杀菌剂复配，通过“多药多靶点”方案获得了具有协同增效作用和潜在的多靶点效应的混剂配方。该研究获得的分子和增效配方有望作为植物病原真菌抗性治理产品开发应用，为植物病害的科学防控提供技术支撑。