双烟碱衍生物作为胆碱酯酶和<i>β</i>-淀粉样蛋白 双功能抑制剂的设计、合成及活性

双烟碱衍生物作为胆碱酯酶和β-淀粉样蛋白双功能抑制剂的设计、合成及活性

摘要: 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1.67 μmol·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20 μmol·L^-1浓度下能够明显抑制β-淀粉样蛋白(β-Amyloid, Aβ )的自聚集。

Abstract: A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC₅₀, 2.28-117.86 μmol·L^-1 for AChE and 1.67-125 μmol·L^-1 for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Aβ aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 μmol·L^-1.