咪唑烷二酮系列衍生物的合成及其抗炎活性的初步研究-药学;药理学专业毕业论文.docx

天津医科人学硕士学位论文中文摘要 天津医科人学硕士学位论文 中文摘要 目的：过氧化物酶体增殖物激活受体、基质金属蛋白酶、磷酸二酯酶4 等蛋白质分子，在炎症介质生成、向炎症部位游走及诱发炎症反应过程中发挥 了重要作用。本试验以上述酶类为靶标，利用分子对接技术，对设计的咪唑烷 二酮衍生物进行虚拟筛选；选择代表性分子进行合成，对所得化合物的抗炎活 性进行初步研究，旨在发现理想的抗炎药物。 方法：首先对过氧化物酶体增殖物激活受体等炎症相关受体的蛋白结构 进行序列比对、立体结构叠合，分析其亲缘性和代表性，选择代表性分子作为 对接计算的模板：对咪唑烷二酮母体结构进行设计改造，利用对接计算的方法， 选出目标分子进行合成；以苯胺系列衍生物为主要原料，合成目标化合物；利 用巴豆油致小鼠耳肿和醋酸致小鼠扭体两个模型对目标化合物的抗炎镇痛活性 进行了初步筛选。 结果：找到了适用于理论筛选的代表性靶酶结构；以咪唑烷二酮为母核 进行了分子设计和结构改造，对自行设计的化合物分子库进行筛选；确定以苯 胺类化合物为起始合成目标化合物，合成得到了十个新化合物；药理活性试验 显示，有三个化合物对巴豆油引起的小鼠急性耳肿有显著的抑制作用。 结论：本试验建立了化合物抗炎活性虚拟筛选模型；通过结构设计改造 和对接计算，虚拟筛选得到了目标分子；合成具有代表性的化合物，经药理试 验验证部分目标化合物具有一定的抗炎活性，表明基于酶结构的新药设计具有 一定的可行性。 关键词：过氧化物酶体增殖物激活受体基质金属蛋白酶磷酸二酯酶 4脂氧合酶环氧合酶对接计算抗炎镇痛 天津医科大学硕士学位论文Abstract 天津医科大学硕士学位论文 Abstract Obj ective：PPAR—og一{i／-V，MMPs，PDE4 and LOX play significant roles in anti-inflammatory progress，such弱the production and migration of inflammatory mediators 8．S well嬲the inflammatory injuries induced by these mediators．Based on the 3D structures of these protein molecules，novel anti—inflammatory compounds were anticipated to be development in this research by molecular modification and virtual screening of imidazolidine-2，4一dione and its derivatives． Methods：Sequence alignments of primary structures，3D structure fitting and phylogenetic．relationship analysis of these enzymes have been performed to choose the representative structure；eight enzymes were chose for docking．According to the results of molecule docking of imidazolidine-2，4一dione and its derivatives，target compotmds were selected and designed to be acquired by organic synthesis．Aniline and its derivatives were the main raw materials of synthesis．Anti—inflammatory and analgesic activities were evaluated respectively by mice ear swelling model induced by croton oil and mice writhing test induced by acetic acid． Results：Representative receptor molecules that suit for virtual screening were found．Target molecules were selected from imidazolidine．2，4．dione and its derivatives through molecular modification and virtu