天然产物Pimprinine的结构优化及其衍生物的杀菌活性研究

Natural product based lead discovery for pesticide development is a hotspot and frontier in the field of agrochemicals in recent years. Pimprinine together with its derivatives, as a class of active natural products, has been reported to display a variety of biological activities. While, the agricultural antifungal activity of Pimprinine have rarely been reported before. In our previous study, we reported Pimprinine and its derivatives exhibited good antifungal activity. In this research, we will use Pimprinine as the lead compound and focus on the systematic structural optimization, including combination of the structural properties of Pimprinine and other similar natural products, replacement of indole with other active heterocycles, changing the link site of indole and oxazole, introducing a bridge between the indole and oxazole rings, or introducing a substructure of thio-containing oxadiazole, to design and synthesize a series of novel Pimprinine derivatives, test their antifungal activity, carry out the computer-aided 3D-QSAR (Three Dimension Quantitative Structure-Activity Relationship) study, and make the further structural optimization, to obtain some highly active Pimprinine compounds for the study of mechanism of action and development of novel fungicide.

以天然产物为先导化合物而进行的农药分子开发，是近年来农药领域的一个热点和前沿方向。Pimprinine及其衍生物作为一类活性天然产物，被报道具有广泛的生物活性，但是在农业杀菌剂领域鲜有报道。在前期工作中，我们发现Pimprinine及其衍生物表现出了较好的杀菌活性。本项目将在前期工作基础上，以Pimprinine为先导结构，对其骨架的各个位点进行系统的优化改造，包括合成含Pimprinine和其他类似天然产物结构特点的化合物，其他活性杂环替换吲哚，改变吲哚和噁唑连接位点，在吲哚和噁唑之间引入桥结构，以及引入含硫噁二唑亚结构，设计并合成一系列新型的Pimprinine衍生物，测试其杀菌活性，采用计算机辅助的方式进行三维定量构效关系(3D-QSAR)研究，并进一步优化结构，从而获得高活性的Pimprinine类化合物，为作用机理研究乃至新型绿色杀菌剂开发提供分子基础。

以天然产物为先导化合物而进行的农药分子开发，是近年来农药领域的一个热点和前沿方向。本项目将在前期工作基础上，以Pimprinine为先导结构，对其骨架的各个位点进行系统的优化改造，包括合成含Pimprinine和其他类似天然产物结构特点的化合物，将噁唑替换为咪唑环，在吲哚上引入取代基，将吲哚替换为其他活性杂环，以及苯并吡咯（吲哚）替换为同为苯并五元环的苯并硼唑结构，进行了分子对接实验，设计并合成五个系列新型的Pimprinine衍生物，测试其杀菌活性，并进一步优化结构，构建了目标化合物分子库，开发得到一批化合物杀菌活性优于商品化对照药剂，体现出很好的研究价值和应用潜力。