N-酰基噻唑类衍生物的合成及其对乙酰胆碱酯酶的抑制活性研究

发布时间：2018-04-03 12:32

本文选题：阿尔茨海默病　切入点：乙酰胆碱酯酶　出处：《河北大学》2014年硕士论文

【摘要】：阿尔茨海默病(AD)是一种慢性神经退行性疾病，主要特征是认知和记忆功能不断恶化，日常生活能力减退，并有各种行为障碍。随着世界人口老龄化加剧，AD的发病率逐年增高。目前临床上主要是通过抑制剂抑制乙酰胆碱酯酶(AChE)的活性从而增加人体脑内乙酰胆碱(ACh)的水平，，改善患者的认知和记忆功能。本文针对新的乙酰胆碱酯酶抑制剂的开发，设计合成了14个新的2-氨基-4-苯基噻唑类化合物，通过核磁共振氢谱、质谱、红外光谱等对化合物进行了结构鉴定，并且对化合物初次进行体外乙酰胆碱酯酶抑制活性实验，其中8a表现出较好的AChE抑制活性，其IC50=3.54μmol/L。同时又设计合成了18个新的N-酰基-硫色烯并噻唑-2-胺类化合物，通过核磁共振氢谱、质谱、红外光谱等对化合物进行了结构鉴定，并且进行了体外乙酰胆碱酯酶抑制活性试验，21a的AChE抑制活性最好，IC50=7.92μmol/L。8a和21a的活性都优于对照药利斯的明。为了研究化合物对乙酰胆碱酯酶的作用机制，对活性最好的化合物8a进行了酶促动力学试验，实验结果表明：该化合物是混合型竞争抑制类型，可能同时作用于AChE的两个活性位点。
[Abstract]:Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by deterioration of cognitive and memory functions, decline in daily life, and various behavioral disorders.With the aging of the world population, the incidence of AD is increasing year by year.At present, the inhibition of acetylcholinesterase (ache) activity by inhibitors increases the level of acetylcholine choline (ache) in human brain and improves the cognitive and memory function of patients.In this paper, 14 new 2-amino-4-phenylthiazole compounds were designed and synthesized for the development of new acetylcholinesterase inhibitors. The structures of the compounds were identified by NMR, MS and IR spectra.The inhibitory activity of acetylcholinesterase was tested in vitro for the first time. The inhibitory activity of acetylcholinesterase (IC50=3.54 渭 mol / L) was better in 8 years.At the same time, 18 new N-acyl-thiolyl thiazole-2-amine compounds were designed and synthesized. The structures of the compounds were characterized by NMR, MS and IR spectra.The inhibitory activity of AChE for 21 years was better than that of Listigmine for 21 years. The inhibitory activity of IC50, 7. 92 渭 mol/L.8a and 21 a was superior to that of the control drug Listigmine, and the inhibitory activity of acetylcholinesterase in vitro was tested.In order to study the action mechanism of the compound on acetylcholinesterase, the best active compound 8a was tested by enzymatic kinetic test. The results showed that the compound was a mixed type of competitive inhibition.It may act on two active sites of AChE at the same time.
【学位授予单位】：河北大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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