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Open AccessArticle

Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0596, USA
Author to whom correspondence should be addressed.
Academic Editors: Diego Muñoz-Torrero and Michael Decker
Molecules 2018, 23(12), 3252;
Received: 25 October 2018 / Revised: 27 November 2018 / Accepted: 7 December 2018 / Published: 8 December 2018
(This article belongs to the Special Issue Molecules against Alzheimer II)
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-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 EeAChE (IC50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC50 = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against HsAChE and was found to be even more active than donepezil and inhibited HsAChE better than EeAChE. 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. View Full-Text
Keywords: Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; β-secretase; inhibitors Alzheimer’s disease; acetylcholinesterase; butyrylcholinesterase; β-secretase; inhibitors
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MDPI and ACS Style

Green, K.D.; Fosso, M.Y.; Garneau-Tsodikova, S. Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors. Molecules 2018, 23, 3252.

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