【作者】 盛荣；

【导师】 胡永洲；

【作者基本信息】 浙江大学 ， 药物分析学， 2005， 博士

【摘要】 第一部分:茚酮类AChE抑制剂的设计、合成和构效关系研究 阿尔采默氏病（Alzheimer’s disease,AD）目前已经成为继心脑血管疾病、恶性肿瘤、中风之后的第四大“杀手”。临床治疗AD最有效的是乙酰胆碱酯酶抑制剂（Acetylcholinesterase Inhibitor,AChE）,但是已经上市的药物都存在一定的不足,因此研制新一代的AChE抑制剂是新药研究的迫切任务。 通过对AChE晶体以及多奈哌齐-AChE复合物晶体结构的分析研究,从AChE具有外周和中心两个活性位点的结构特性出发,分别保留多奈哌齐中的二甲氧基茚酮（与外周位点结合）和利伐司替明中的苄基胺（与中心位点结合）药效团,通过氧原子或碳原子进行连接,设计并合成了苯氧茚酮、苯亚甲基茚酮和苄基茚酮类三类新型的AChE抑制剂48个。预期这些化合物能够同时作用于AChE的两个活性位点,不仅能显著抑制脑内乙酰胆碱的水解,提高ACh浓度,而且还能抑制由AChE引起的Aβ聚集,起到更好治疗AD的作用。 这48个新化合物的体外AChE抑制活性实验表明:绝大多数化合物都具有较强的AChE抑制活性,其中3个化合物的IC₅₀达到30～50nmol/L,与多奈哌齐在同一数量级。 为了进一步了解化合物与AChE蛋白的三维空间结合方式,以及为今后合理设计新的衍生物提供理论指导,选择苯氧茚酮类衍生物中活性最高的化合物53进行分子对接研究,发现分子可以通过4个主要官能团与酶进行结合,不仅能够同时作用于AChE的双活性中心,而且与酶的中间通道部分也有结合。并在此基础上开展了苯氧茚酮类衍生物的三维构效关系研究,分别用CoMFA和CoMSIA法建立了苯氧茚酮类化合物的3D-QSAR模型,相关系数R²分别为0.999和0.984,说明模型具有较高的预测能力,对该类化合物的构效关系进行进一步的总结,为进一步的药物设计和结构优化提供了理论依据。更多还原

【Abstract】 Part Ⅰ: Design, synthesis and QSAR study of indan-1-one derivatives as AChE inhibitorsAlzheimer’s disease （AD） has been one of the most severe health problems of the elderly. Acetylcholinesterase （AChE） inhibitors are the first and the most developed group of drugs approved for AD symptomatic treatment. Unfortunatedly, all the drugs used in clinic only showed modest effects. So we are interested in searching for new AChE inhibitors.The crystallographic structure of AChE exhibits that it contains peripheral anionic site and central site. It has been pointed out recently that AChE may be responsible for several noncatalytic actions besides hydrolysis Ach, such as: accelerating β-amyloid peptide deposition, and this function only related with the peripheral anionic site （PAS）. Therefore, molecules able to interact both central and peripheral binding sites may prevent the catalytic and noncatalytic actions of AChE. Following this reasoning, 5,6-dimethoxy-indan-1-one from donepezil （interacting with the peripheral site of AChE）, dialkylbenzylamine from rivastigmine （interacting with the centric site of AChE） were chosed as the two pharmacophoric moieties, and linked with O, =CH and CH₂. Thus, series of 2-phenoxy-indan-1-one, 2-benzylidene-indan-1-one and 2-benzyl-indan-1-one derivatives were designed, synthesized and tested for their AChE inhibitory activity. Most of these derivatives exhibited high AChE inhibitory activity in vitro, and the IC50 values of three compounds were closed to that of Donepezil. The research of their bioactivity in vivo is going on.Compound 53 was picked out to carried out molecular docking study to understand the binding mode in AChE, and results showed that it made principal interactions along the active gorge of the enzyme through four major functional groups: phenyl and oxygen of indan-1-one, phenyl of benzyl group, charged nitrogen of pyrrolidine. On the basis of this founding, the CoMFA and CoMSIA models of 2-phenoxy-indan-1-one derivatives were built and explain the structure-activity relationships in detail. These results will give us some useful indications in the design of new drugs.Part II: Studies on the synthesis of DonepezilDonepezil was the most widely used AChE inhibitor in clinic. To study and improve the method of producing Donepezil, a novel and efficient method was developed to synthesize N-benzyl-4-formyl-piperidine, key intermediate of Donepezil. N-Benzyl -4-piperidone was reacted with dimethyloxo sulfonium methylide to get epoxide, followed by rearrangement in the presence of magnesium bromide etherate to give the aldehyde in high yield. Then it was condensed with 5,6-dimethoxy-indan-l-one to yield a,P-unsaturated ketone, followed by selective hydrogenation with 5% Pd/C and hydrochlorination to yield Donepezil. This synthesis route avoids using expensive reagents such as n-BuLi, LDA, and there is no need to use column chromatograph in all steps.更多还原