论文部分内容阅读
本文设计合成了一系列双烟碱衍生物(3a~3i)作为双功能的抗阿尔茨海默症药物。活性测试结果表明这类衍生物对乙酰胆碱酯酶(acetylcholinesterase,AChE)和丁酰胆碱酯酶(butyrylcholinesterase,BChE)的抑制活性达到微摩尔级,其中化合物3f活性最强,对AChE和BChE的IC50值分别为2.28和1.67μmol·L 1,优于对照药物rivastigmine。酶动力学及分子对接表明3f能够同时作用于AChE的催化活性位点(catalytic active site,CAS)和外周结合位点(peripheral anionic site,PAS)。而且这类衍生物在20μmol·L 1浓度下能够明显抑制β-淀粉样蛋白(β-Amyloid,Aβ)的自聚集。
In this paper, a series of bis-nicotine derivatives (3a ~ 3i) were designed and synthesized as bifunctional anti-Alzheimer's drugs. The results of the activity test showed that these derivatives have micromolar inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), among which compound 3f has the strongest activity and the IC50 of AChE and BChE Values were 2.28 and 1.67μmol·L 1, respectively, better than the control drug rivastigmine. Enzyme kinetics and molecular docking showed that 3f can act on the catalytic active site (AChE) and peripheral anionic site (PAS) simultaneously. Moreover, such derivatives can significantly inhibit the self-aggregation of β-Amyloid (Aβ) at a concentration of 20 μmol·L -1.