杀灭鱼类单殖吸虫木脂素类化合物的合成及构效关系研究

长期以来，杀灭单殖吸虫的渔药主要是有机磷农药、甲苯咪唑等，由于产生的耐药性、水产品安全和生态安全一系列问题，业已成为制约单殖吸虫病害控制的瓶颈。天然产物活性及其构效关系研究是药物研发的理论基础，也是创制无公害渔药、控制水产养殖病害发生、保障食品与水环境安全的重要途径之一。本项目以木质素类化合物为研究对象，采用3,4-二羟基苯甲醛、溴化苄、琥珀酸二甲酯为原料，通过氧化、还原、缩合等方法合成二苄基丁内酯型的木脂素类骨架（母环），再通过甲基化、酯化、糖基化等手段合成一系列木脂素类化合物，结合药效学测定，进行构效关系研究，阐明杀虫活性相关功能基团和对鱼致毒基团；根据合成化合物的杀虫参数建立QSAR模型进行理论验证，建立快速可行的木脂素类杀虫药物分子设计预测和筛选方法。该项目的开展不但为鱼类寄生虫木脂素类药物研究奠定理论基础，同时也为今后无公害渔药基础创新与创制提供新思路和模板，具有重要的应用前景。

Nowadays, the drugs against monogenean parasites are mainly phosphate and mebendazole chemicals. The application of these chemical-based agents has had limited efficacy due to the raised drug-resistance caused by the frequent use of these drugs. Hence, the lack of research and application of parasiticidal bulk drugs has become the bottleneck for the control of monogenean parasites diseases. The study of natural active compounds is one of important approaches to develop new pollution-free aquacultural drugs, control aquaculture diseases, as well as guarantee the security of food and environment. In this project, dibenzylbutyrolactone skeleton of lignin were obtained by total synthesis from 3,4-dihydroxybenzaldehyde, benzyl bromide and dimethyl succinate through oxidation, reduction and condensation reaction. A series of lignans derivatives were then obtained by means of one-step methylation, esterification or glycosylation of dibenzylbutyrolactone skeleton, specifically determining the functional groups with parasiticidal activity and toxicity groups to fish through the research of the structure-activity relationship which can be achieved by the synthesis of lignans derivatives and detection their parasiticidal activity. Quantitative structure-activity relationship models (QSAR) were established to predict the parasiticidal activity of the synthetic compounds for the sake of setting up a fast and feasible method for the design, prediction and screening of lignan parasiticides. This research not only lays the theoretical foundation for the development of lignan drugs against fish parasites, but also provides new ideas for the innovation and creation of base for the pollution-free fishery drugs in the future, which has an important application prospect.