Multifunctional donepezil analogues as cholinesterase and BACE1 inhibitors

Keith D. Green; Marina Y. Fosso; Sylvie Garneau-Tsodikova

doi:10.3390/molecules23123252

Multifunctional donepezil analogues as cholinesterase and BACE1 inhibitors

Keith D. Green
, Marina Y. Fosso
, Sylvie Garneau-Tsodikova

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

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 (IC ₅₀ = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC ₅₀ = 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.

Original language	English
Article number	3252
Journal	Molecules
Volume	23
Issue number	12
DOIs	https://doi.org/10.3390/molecules23123252
State	Published - Dec 8 2018

Bibliographical note

Publisher Copyright:
© 2018 by the authors.

Funding

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.

Funders	Funder number
California State University	P41-GM103311
California State University
University of Kentucky
College of Pharmacy

Keywords

Acetylcholinesterase
Alzheimer’s disease
Butyrylcholinesterase
Inhibitors
β-secretase

ASJC Scopus subject areas

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

Access to Document

10.3390/molecules23123252

Cite this

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title = "Multifunctional donepezil analogues as cholinesterase and BACE1 inhibitors",

abstract = " 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{\textquoteright}s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC 50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC 50 = 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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note = "Publisher Copyright: {\textcopyright} 2018 by the authors.",

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doi = "10.3390/molecules23123252",

language = "English",

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AU - Green, Keith D.

AU - Fosso, Marina Y.

AU - Garneau-Tsodikova, Sylvie

PY - 2018/12/8

Y1 - 2018/12/8

N2 - 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 (IC 50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC 50 = 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.

AB - 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 (IC 50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC 50 = 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.

KW - Acetylcholinesterase

KW - Alzheimer’s disease

KW - Butyrylcholinesterase

KW - Inhibitors

KW - β-secretase

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DO - 10.3390/molecules23123252

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SN - 1420-3049

VL - 23

JO - Molecules

JF - Molecules

IS - 12

M1 - 3252

ER -

Multifunctional donepezil analogues as cholinesterase and BACE1 inhibitors

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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