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.

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Notes/Citation Information

Published in Molecules, v. 23, issue 12, 3252, p. 1-22.

© 2018 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Funding Information

This work was supported by startup funds (to S.G.-T.) from the College of Pharmacy at the University of Kentucky. Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.

Related Content

The Supplementary Materials include 1H and 13C-NMR spectra for the molecules synthesized, as well as HPLC traces of compounds tested for activity (Figures S1–S81). The IC50 curves for the inhibition of EeAChE, HsAChE, EfBChE, and BACE1 are also provided (Figures S82–S87). The SwissDock modeling is also provided (Figure S88). These materials are available free of charge via the internet.

Sample Availability: Samples of the compounds synthesized are available from the authors.

molecules-23-03252-s001.pdf (8592 kB)
Supplementary Material