Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors

A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-<i>O</i>-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes respons...

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Bibliographic Details
Main Authors: Keith D. Green, Marina Y. Fosso, Sylvie Garneau-Tsodikova
Format: Article
Language:English
Published: MDPI AG 2018-12-01
Series:Molecules
Subjects:
Online Access:https://www.mdpi.com/1420-3049/23/12/3252
Description
Summary:A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-<i>O</i>-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&#8217;s disease patient brains. Many of them displayed lower inhibitory concentrations of <i>Ee</i>AChE (IC<sub>50</sub> = 0.016 &#177; 0.001 &#181;M to 0.23 &#177; 0.03 &#181;M) and <i>Ef</i>BChE (IC<sub>50</sub> = 0.11 &#177; 0.01 &#181;M to 1.3 &#177; 0.2 &#181;M) than donepezil. One of the better compounds was tested against <i>Hs</i>AChE and was found to be even more active than donepezil and inhibited <i>Hs</i>AChE better than <i>Ee</i>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 &#946;-secretase (BACE1) enzyme.
ISSN:1420-3049