半乳呋喃糖类似物的设计、合成和活性评价

发布时间：2018-01-17 20:29

本文关键词：半乳呋喃糖类似物的设计、合成和活性评价　出处：《华北理工大学》2015年硕士论文　论文类型：学位论文

【摘要】：目的设计、合成二磷酸尿苷-半乳糖变位酶受体类似物2-(1,2-二羟基-乙基)-吡咯烷-3,4-二醇和2-(1,2-二羟基-乙基)-5-甲基-吡咯烷-3,4-二醇,评价其与二磷酸尿苷-半乳糖变位酶分子对接及体外抗结核活性。方法运用逆向合成分析思路,设计合成路线;以D-半乳糖为手性源,经过羟基保护用苄基、甲苷水解、引入氮源,分子内环合等多步反应完成重要中间体——环状硝酮的制备,直接催化氢化得到2-(1,2-二羟基-乙基)-吡咯烷-3,4-二醇;环状硝酮与Grignard试剂进行高立体选择性加成反应,再经催化氢化完成了2-(1,2-二羟基-乙基)-5-甲基-吡咯烷-3,4-二醇的合成;运用分子对接方法,预测其与二磷酸尿苷-半乳糖变位酶的结合活性;采用二倍稀释法,以异烟肼为阳性药物,测定两个目标化合物对结核分枝杆菌标准株H37Rv的最小抑菌浓度。结果按照预定的合成路线,完成目标化合物制备,经氢谱佐证。运用计算机模拟目标化合物与二磷酸尿苷-半乳糖变位酶的分子对接,得到结果:2-(1,2-二羟基-乙基)-吡咯烷-3,4-二醇的分子对接总分数为5.1510;2-(1,2-二羟基-乙基)-5-甲基-吡咯烷-3,4-二醇的分子对接总分数为2.8797,说明前者较后者与二磷酸尿苷-半乳糖变位酶有更好的亲和力。体外抗结核活性实验结果:2-(1,2-二羟基-乙基)-吡咯烷-3,4-二醇的MIC值为0.048μg/m L;2-(1,2-二羟基-乙基)-5-甲基-吡咯烷-3,4-二醇的MIC值为0.097μg/m L,显示前者较后者有较好的抑菌活性。结论以D-半乳糖为原料,环状硝酮为中间体完成2-(1,2-二羟基-乙基)-吡咯烷-3,4-二醇和2-(1,2-二羟基-乙基)-5-甲基-吡咯烷-3,4-二醇的制备。两种目标化合物对结核分枝杆菌标准株均有一定的抑制作用,且前者比后者的抑制效果更好,与分子对接的结果一致,表明两者可能是通过二磷酸尿苷-半乳糖变位酶实现其抗结核活性的,为新型抗结核药的研发提供了新思路。
[Abstract]:Objective to design and synthesize uridine diphosphate galactose receptor analogue 2-O1O2-dihydroxy-ethyl-keto-pyrrolidine 4-diol and 2-tio 1. Methods 2-dihydroxy-ethyl-5-methyl-pyrrolidine 4-diol was used to evaluate its docking with uridine diphosphate galactose mutagenase molecule and its antituberculous activity in vitro. Design synthetic route; With D-galactose as chiral source, the important intermediate, cyclonitrone, was prepared by multi-step reactions such as hydroxy protection benzyl, methyl-glucoside hydrolysis, introduction of nitrogen source and intramolecular cyclization. 2-dihydroxy-2-ethyl-pyrrolidine 4-diol was synthesized by direct hydrogenation. Cyclic nitrone reacted with Grignard reagent with high stereoselective addition reaction and then was hydrogenated to complete 2-dihydroxy-2-ethyl-5-methyl-pyrrolidine-3 by catalytic hydrogenation. Synthesis of 4-diol; Molecular docking method was used to predict its binding activity with uridine diphosphate galactose-galactose mutase. The minimal inhibitory concentration of two target compounds against Mycobacterium tuberculosis standard strain H37Rv was determined by double dilution method with isoniazid as positive drug. The target compound was prepared and proved by hydrogen spectrum. The molecular docking of the target compound with uridine diphosphate galactose mutase was simulated by computer and the result was obtained. The total molecular docking fraction of 2-dihydroxy-ethyl-pyrrolidine -3O4-diol is 5.1510; The total molecular docking fraction of 2-dihydroxy-2-ethyl-2-methyl-5-methyl-pyrrolidine 4-diol is 2.8797. The results showed that the former had better affinity to uridine diphosphate galactose-galactose mutase than the latter. The results of in vitro antituberculous activity test showed that the former had better affinity to uridine diphosphate-galactose-3-dihydroxy-2-dihydroxy-2-ethyl-pyrrolidine-3. The MIC of 4-diol was 0.048 渭 g / mL; The MIC value of 2-dihydroxy-2-ethyl-2-methyl-5-methyl-pyrrolidine 4-diol is 0.097 渭 g / mL. Conclusion using D-galactose as the raw material and cyclic nitrone as the intermediate, the two dihydroxy-2-dihydroxy-ethyl-pyrrolidine 4-diol and 2-butane-1-diol were completed. Preparation of 2-dihydroxy-ethyl-5-methyl-pyrrolidine 4-diol. The two target compounds have a certain inhibitory effect on the standard strains of Mycobacterium tuberculosis, and the former is better than the latter. In accordance with the results of molecular docking, it is suggested that both of them may achieve their antituberculous activity by uridine diphosphate galactose mutagenase, which provides a new idea for the research and development of novel antituberculous drugs.
【学位授予单位】：华北理工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R91;R914.5

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