基于药效评价模型的建立筛选抗寄生原虫植物源活性分子

Taking pharmacology activity molecules from natural products as templates, a study on the structure-activity relationship and the computer assisted optimization design is performed, which provides a shortcut to develop the green fishery drugs. Screening and isolating the activity molecules from botanicals is the basis for further botanical drug development in aquaculture. The parasitic protozoan Ichthyophthirius multifiliis probably accounting for more damage to freshwater fish populations worldwide than any other eukaryote pathogen, was used to the research object for this project. According to different characteristics of life cycle and infestation of this parasite, a series of pharmacodynamical evaluation models for in vitro and in vivo were built based on the optimization of sereral important conditions affecting drug activity detection. Under the guidance of antiparasitic activity detected by the above models, the activity molecules were separated by absorption chromatography、gel permeation chromatography、high performance liquid chromatography、gas chromatography and their separation techniques from botanicals with potential antiparasitic activity based on our preliminary study and reports, and the structures of these molecules were determined through the spectrum analysis、chemical elements analysis and the other analysises; meanwhlie, antiparasitic activity of several molecules obtained from our preliminary study was also determined. This study tries to identify botanical antiparasitic molecules in order to provide some reference for creation of bulk pharmaceuticals in aquaculture. Also, it may provide a novel idea and model for development of green fishery drug, and is of profound theoretical and practical significance.

以天然产物活性分子为模板，通过进行构效关系及计算机辅助优化设计研究，是创制无公害渔药的一条重要途径，其中从植物中分离筛选获得活性分子是开发无公害渔药的基础和前提。本项目以对鱼类危害最大的寄生原生动物之一的小瓜虫为研究对象，依据其生活史和感染的不同特点对影响药物活性检测的几个重要因素进行最适化探讨，并依此建立药效评价体外和感染动物模型。以此模型检测的抗虫活性为指导，对前期研究初步筛选的具有潜在抗虫活性的目标中草药应用吸附柱色谱、凝胶柱色谱、高效液相色谱、气相色谱等分离技术进行抗虫活性分子分离筛选研究，并最终通过波谱解析、化学元素分析等分析技术对其结构进行鉴定；或直接活性检测确定前期研究分离筛选的活性分子的抗虫活性，以期筛选出植物源抗寄生原虫活性分子。该项目的研究可以为新渔药原料药的创制提供借鉴。同时，也为今后无公害渔药的创新研究提供新思路和新方法，具有重要的科学理论意义和应用前景。

以天然产物活性分子为模板，通过构效关系研究及结构优化改造，是创制无公害渔药的一条重要途径，其中从植物中分离筛选活性分子是开发无公害渔药的基础和前提。本项目以对鱼类危害最大的寄生原生动物之一的小瓜虫为研究对象，首先根据其生活史的特点以及影响药物活性检测的几个重要因素建立了药效评价体外和感染动物模型；其次，基于该药效评价模型从近80种药用植物中筛选得到2种同时具有离体和在体抗虫活性的药用植物：补骨脂（Psoralea corylifolia）和厚朴（Magnolia officinalis）；其后，我们运用活性跟踪指导分离法及现代波谱技术，成功从2种药用植物中分离得到4种最优抗虫活性分子：补骨脂定（psoralidin）、补骨脂甲素（psoralen）、厚朴酚（magnolol）、和厚朴酚（honokiol），其中活性分子厚朴酚不仅具有最优的离体和在体抗虫效果，而且其简单的化学结构、易人工全合成且合成成本低的特点使得厚朴酚在目前已经发现的活性天然产物中具有较高的应用价值。此外，我们还运用有机化学合成的方法得到了六种厚朴酚的同分异构体及类似物，后续的活性评价结果表明，厚朴酚苯环上的羟基对离体抗虫活性起到了关键作用，而苯环上的烯丙基直接关系到其在体抗虫活性的高低。该项目的研究不仅为今后抗虫活性分子的结构修饰和改造提供参考和依据，而且可以为新渔药原料药的创新创制提供新思路和新方法，具有重要的科学理论意义和应用前景。