Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA.
Molecules. 2018 Dec 8;23(12):3252. doi: 10.3390/molecules23123252.
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6--desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer's disease patient brains. Many of them displayed lower inhibitory concentrations of AChE (IC = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and BChE (IC = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against AChE and was found to be even more active than donepezil and inhibited AChE better than AChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme.
合成了一系列 22 种多奈哌齐类似物，通过烷基化/苄基化进行比较，并与多奈哌齐及其 6--去甲基加合物进行比较。所有化合物均被发现是乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 的有效抑制剂，这两种酶负责水解阿尔茨海默病患者大脑中的神经递质乙酰胆碱。其中许多化合物对 AChE（IC=0.016±0.001µM 至 0.23±0.03µM）和 BChE（IC=0.11±0.01µM 至 1.3±0.2µM）的抑制浓度均低于多奈哌齐。对其中一种较好的化合物进行了 AChE 抑制测试，发现其比多奈哌齐更具活性，并且比 AChE 更好地抑制 AChE。具有芳香取代基的类似物通常比具有脂肪族取代基的类似物更有效。其中 5 种类似物也抑制了β-分泌酶（BACE1）酶的活性。
