治疗阿尔茨海默症的多靶点药物分子的设计、合成及构效关系研究
发布时间：2019-02-12 12:39
【摘要】：阿尔茨海默症(Alzheimer’s Disease,AD),最常见的痴呆类型,是一种慢性神经退行性疾病,其临床特征表现为记忆损伤,认知复杂,语言障碍,情绪不稳和行为异常等。乙酰胆碱(Acetylcholine,ACh)和?淀粉样蛋白(Amyloid?-protein,A?)沉积水平在AD的发生、发展过程中起重要作用。虽然AD的发病机制尚未完全了解,目前认为AD的最有效的治疗方法是增强大脑中的胆碱能神经传递并降低ACh水解;另外,保护神经细胞免受Aβ诱导的细胞损伤和凋亡,对预防及治疗AD也具有积极的作用。相对于单靶点药物,多靶点药物可针对疾病的不同生理环节发挥作用并且具有不良反应少、临床使用剂量低、疗效显著等优点。本课题把结构骨架新颖且具有较好乙酰胆碱酯酶抑制活性的三氮唑化合物MX-1作为先导化合物,对其进行结构修饰合成了一批衍生物。然后我们对目标化合物做了相关体外活性测试,得到具有潜在抗AD活性的化合物39:该化合物对AChE表现出较强的抑制作用,IC50为7.23μM;对Keap1-Nrf2蛋白相互作用具有一定的抑制活性;对A?25-35诱导的神经细胞SH-SY5Y损伤具有较好的保护活性,浓度在10μM时,细胞存活率达到了96.5%;对正常细胞系(HaCaT细胞系和NIH-3T3细胞系)没有明显的细胞毒作用;虚拟对接表明,该化合物与AChE活性位点氨基酸残基具有很好的结合作用;物化性质预测表明该类化合物具有合适的透过血脑屏障能力。本课题为设计高效、低毒的新型多靶点抗AD药物提供分子模型和理论依据,对研发出有效的抗AD药物具有十分重要的意义,值得继续深入研究。
[Abstract]:Alzheimer's disease (Alzheimer's Disease,AD), the most common type of dementia, is a chronic neurodegenerative disease characterized by memory impairment, cognitive complexity, language disorders, emotional instability and behavioral abnormalities. Acetylcholine (Acetylcholine,ACh) and? Amyloid protein (Amyloid?-protein,A?) Sedimentary level plays an important role in the occurrence and development of AD. Although the pathogenesis of AD has not been fully understood, it is believed that the most effective treatment for AD is to enhance cholinergic nerve transmission in the brain and reduce ACh hydrolysis. In addition, protecting neurons from A 尾 -induced cell damage and apoptosis also plays an active role in the prevention and treatment of AD. Compared with single target drugs, multi-target drugs can play a role in different physiological aspects of disease and have the advantages of less adverse reactions, low clinical dosage and remarkable curative effect. A series of derivatives were synthesized by structural modification of triazole compound MX-1, which has novel structure skeleton and good inhibitory activity of acetylcholinesterase. Then we tested the activity of the target compound in vitro and got the compound 39 with potential anti-AD activity. The compound showed a strong inhibitory effect on AChE, IC50 was 7.23 渭 m; It has a certain inhibitory activity on the interaction of Keap1-Nrf2 protein and a good protective activity against the SH-SY5Y damage induced by AZ25-35. The survival rate of the cells reached 96.5when the concentration of 10 渭 M was 10 渭 M. There was no obvious cytotoxic effect on normal cell line (HaCaT cell line and NIH-3T3 cell line), and virtual docking showed that the compound had a good binding effect with the amino acid residues of AChE active site. The prediction of physicochemical properties indicates that the compounds have the appropriate ability to penetrate the blood-brain barrier. This paper provides a molecular model and theoretical basis for the design of new multi-target anti-AD drugs with high efficiency and low toxicity. It is of great significance for the development of effective anti-AD drugs and is worthy of further study.
【学位授予单位】：济南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
本文编号：2420451
[Abstract]:Alzheimer's disease (Alzheimer's Disease,AD), the most common type of dementia, is a chronic neurodegenerative disease characterized by memory impairment, cognitive complexity, language disorders, emotional instability and behavioral abnormalities. Acetylcholine (Acetylcholine,ACh) and? Amyloid protein (Amyloid?-protein,A?) Sedimentary level plays an important role in the occurrence and development of AD. Although the pathogenesis of AD has not been fully understood, it is believed that the most effective treatment for AD is to enhance cholinergic nerve transmission in the brain and reduce ACh hydrolysis. In addition, protecting neurons from A 尾 -induced cell damage and apoptosis also plays an active role in the prevention and treatment of AD. Compared with single target drugs, multi-target drugs can play a role in different physiological aspects of disease and have the advantages of less adverse reactions, low clinical dosage and remarkable curative effect. A series of derivatives were synthesized by structural modification of triazole compound MX-1, which has novel structure skeleton and good inhibitory activity of acetylcholinesterase. Then we tested the activity of the target compound in vitro and got the compound 39 with potential anti-AD activity. The compound showed a strong inhibitory effect on AChE, IC50 was 7.23 渭 m; It has a certain inhibitory activity on the interaction of Keap1-Nrf2 protein and a good protective activity against the SH-SY5Y damage induced by AZ25-35. The survival rate of the cells reached 96.5when the concentration of 10 渭 M was 10 渭 M. There was no obvious cytotoxic effect on normal cell line (HaCaT cell line and NIH-3T3 cell line), and virtual docking showed that the compound had a good binding effect with the amino acid residues of AChE active site. The prediction of physicochemical properties indicates that the compounds have the appropriate ability to penetrate the blood-brain barrier. This paper provides a molecular model and theoretical basis for the design of new multi-target anti-AD drugs with high efficiency and low toxicity. It is of great significance for the development of effective anti-AD drugs and is worthy of further study.
【学位授予单位】：济南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96
【参考文献】
相关期刊论文 前1条
1 应侠;吴振;雷严;王立强;;阿尔茨海默病的发病机制及治疗药物研究进展[J];中国药房;2014年33期
，本文编号：2420451
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