Hybrid pharmacophore design and synthesis of donepezil-inspired aurone derivative salts as multifunctional acetylcholinesterase inhibitors

Rei Funahashi; Fumiaki Matsuura; Masayuki Ninomiya; Sayo Okabe; Shigeo Takashima; Kaori Tanaka; Atsuyoshi Nishina; Mamoru Koketsu

doi:10.1016/j.bioorg.2024.107229

Hybrid pharmacophore design and synthesis of donepezil-inspired aurone derivative salts as multifunctional acetylcholinesterase inhibitors

Bioorg Chem. 2024 Apr:145:107229. doi: 10.1016/j.bioorg.2024.107229. Epub 2024 Feb 20.

Authors

Rei Funahashi¹, Fumiaki Matsuura¹, Masayuki Ninomiya², Sayo Okabe¹, Shigeo Takashima³, Kaori Tanaka⁴, Atsuyoshi Nishina⁵, Mamoru Koketsu⁶

Affiliations

¹ Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
² Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Division of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
³ Division of Genomics Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; United Graduate School of Drug Discovery and Medicinal Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; Division of Cooperative Research Facility, Institute for Glyco-core Research (iGCORE), Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁴ Division of Anaerobe Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; United Graduate School of Drug Discovery and Medicinal Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; Division of Cooperative Research Facility, Institute for Glyco-core Research (iGCORE), Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁵ College of Science and Technology, Nihon University, Chiyoda, Tokyo 101-0062, Japan; School of Health and Nutrition, Tokai Gakuen University, Tenpaku, Nagoya, Aichi 468-8514, Japan.
⁶ Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: koketsu.mamoru.e0@f.gifu-u.ac.jp.

PMID: 38401360
DOI: 10.1016/j.bioorg.2024.107229

Abstract

Flavonoids, a ubiquitous group of plant polyphenols, are well-known for their beneficial effects on human health. Their phenylchromane skeletons have structural similarities to donepezil [the US FDA-approved drug used to treat Alzheimer's disease (AD)]. The objective of this study was to design and synthesize valuable agents derived from flavonoids for relieving the symptoms of AD. A variety of flavonoid derivative salts incorporating benzylpyridinium units were synthesized and several of them remarkedly inhibited acetylcholinesterase (AChE) activity in vitro. Additionally, aurone derivative salts protected against cell death resulting from t-BHP exposure in rat pheochromocytoma PC12 cells and slightly promoted neurite outgrowth. Furthermore, they potently suppressed the aggregation of amyloid-β (Aβ_1-42). Our findings highlight the effectiveness of donepezil-inspired aurone derivative salts as multipotent candidates for AD.

Keywords: Alzheimer's disease; Amyloid-β aggregation; Aurone; Donepezil; Reactive oxygen species.

MeSH terms

Acetylcholinesterase / metabolism
Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Benzofurans*
Cholinesterase Inhibitors* / chemistry
Donepezil / pharmacology
Donepezil / therapeutic use
Flavonoids / therapeutic use
Humans
Pharmacophore
Rats
Salts
Structure-Activity Relationship

Substances

Donepezil
Cholinesterase Inhibitors
Acetylcholinesterase
aurone
Salts
Amyloid beta-Peptides
Flavonoids
Benzofurans