【摘要】：阿爾茨海默病(Alzheimer’s Disease,AD)是一種慢性神經(jīng)退行性疾病,主要特征是認(rèn)知和記憶功能不斷惡化,日常生活能力減退,并有各種行為障礙。目前商品化的AD治療藥物只能緩解部分AD患者的癥狀,且存在不同程度的副作用。因此,通過(guò)設(shè)計(jì)合成新的化學(xué)實(shí)體,尋找高效、毒副作用小的AChE抑制劑仍然是科研工作者的努力方向。本論文基于乙酰膽堿酯酶抑制劑類(lèi)阿爾茨海默病治療藥物的研究現(xiàn)狀,在系統(tǒng)查閱文獻(xiàn)的基礎(chǔ)上,分別以α-溴代苯乙酮和苯甲酸為原料合成了新的L-脯氨酸和噻二唑衍生物,并采用Ellman分光光度法測(cè)試了它們對(duì)乙酰膽堿酯酶的體外抑制活性。本文中制備的L-脯氨酸和噻二唑衍生物的化學(xué)結(jié)構(gòu)均經(jīng)核磁共振氫譜、高分辨質(zhì)譜、紅外等波譜技術(shù)進(jìn)行了確證。它們對(duì)乙酰膽堿酯酶的體外抑制活性測(cè)試結(jié)果表明:L-脯氨酸衍生物具有較好的乙酰膽堿酯酶抑制活性,其中化合物8b的抑制活性最好,其IC50達(dá)到了5.45μmol·L-1,優(yōu)于對(duì)照藥利斯的明,同時(shí)它對(duì)丁酰膽堿酯酶幾乎沒(méi)有抑制活性;噻二唑衍生物也具有一定的乙酰膽堿酯酶的抑制活性,但活性較差,抑制活性最好的化合物14b的IC50值為15μmol·L-1,低于對(duì)照藥利斯的明。此外,我們對(duì)生物活性較好化合物8b進(jìn)行了酶抑制動(dòng)力學(xué)實(shí)驗(yàn),研究目標(biāo)化合物與AChE的作用機(jī)制。通過(guò)繪制Line weaver-Burk圖,表明化合物8b對(duì)AChE抑制方式為混合型競(jìng)爭(zhēng)性抑制。
[Abstract]:Alzheimer's disease (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. At present, the commercialized AD therapy can only relieve the symptoms of some AD patients, and there are some side effects. Therefore, it is still the direction of researchers to design and synthesize new chemical entities to find AChE inhibitors with high efficiency and low toxicity. Based on the research status of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease, new derivatives of L-proline and thiadiazole were synthesized from 偽 -bromoacetophenone and benzoic acid, respectively. The inhibitory activity of acetylcholinesterase on acetylcholinesterase was measured by Ellman spectrophotometry. The chemical structures of the L- proline and thiadiazole derivatives were confirmed by nuclear magnetic resonance (NMR), high resolution mass spectrometry (HRMS) and infrared spectroscopy (IR). The inhibitory activity of L- proline derivatives on acetylcholinesterase was tested in vitro. The results showed that L- proline derivatives had better inhibitory activity of acetylcholinesterase, and compound 8b had the best inhibitory activity, its IC50 reached 5.45 渭 mol L-1, which was better than that of control drug Listigmine. At the same time, it had little inhibitory activity on butyrylcholinesterase, and thiadiazole derivatives had a certain inhibitory activity of acetylcholinesterase, but the activity was poor. The IC50 value of 14b compound with the best inhibitory activity was 15 渭 mol L -1, which was lower than that of control drug Listigmine. In addition, the enzyme inhibition kinetics of 8b, a good bioactive compound, was studied to study the mechanism of the interaction between the target compound and AChE. The Line weaver-Burk diagram showed that compound 8b could inhibit AChE in a mixed competitive manner.
【學(xué)位授予單位】：河北大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R91;R914
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本文編號(hào)：2272505