Abstract
To find the multi-target-directed compounds for the treatment of Alzheimer's disease (AD), we synthesized 7-(4-(diethylamino)butoxy)-5-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one, a novel 7-O-modified genistein derivative (GS-14), and investigated its acetylcholinesterase (AChE) inhibitory effect, estrogenic activity and neuroprotective effect. GS-14 acted as a selective AChE inhibitor in vitro, with an IC₅₀ value of 0.17 μM and showed no inhibition activity against butyrylcholinesterase (BuChE). The Lineweaver-Burk plot revealed that GS-14 was a non-competitive AChE inhibitor with a K(i) value of 0.23 μM and the molecular docking model indicated that GS-14 interacted with the peripheral anionic site (PAS) of AChE. The MCF-7 proliferation assay demonstrated that GS-14 possessed estrogenic activity and GS-14 exhibited a high specificity for estrogen receptor β (ERβ) with a dissociation constant (K(i)) of 2.86 nM compared with that of 1.01 μM for estrogen receptor α (ERα) in the molecular docking study. GS-14 also possessed a neuroprotective effect and showed the best protective effect against the β-amyloid protein-induced injury on SH-SY5Y cells at a concentration of 1 nM. Considering its AChE-inhibition activity, estrogenic activity and neuroprotective effect, GS-14 may be a potential multi-target agent for the treatment of AD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy
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Amyloid beta-Peptides / antagonists & inhibitors
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Animals
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Cell Line
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Cell Proliferation / drug effects
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / metabolism
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Cholinesterase Inhibitors / pharmacology*
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Drug Design
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Estrogen Receptor alpha / agonists
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Estrogen Receptor alpha / chemistry
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Estrogen Receptor alpha / metabolism
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Estrogen Receptor beta / agonists
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Estrogen Receptor beta / chemistry
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Estrogen Receptor beta / metabolism
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Estrogens, Non-Steroidal / chemistry
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Estrogens, Non-Steroidal / metabolism
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Estrogens, Non-Steroidal / pharmacology*
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Genistein / analogs & derivatives*
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Genistein / chemistry
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Genistein / metabolism
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Genistein / pharmacology
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Humans
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Kinetics
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MCF-7 Cells
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Molecular Conformation
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Molecular Docking Simulation
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Molecular Targeted Therapy
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology*
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Nootropic Agents / chemistry
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Nootropic Agents / metabolism
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Nootropic Agents / pharmacology
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Protein Binding
Substances
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7-(4-(diethylamino)butoxy)-5-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one
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Amyloid beta-Peptides
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Cholinesterase Inhibitors
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ESR1 protein, human
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Estrogens, Non-Steroidal
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Neuroprotective Agents
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Nootropic Agents
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Genistein
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Acetylcholinesterase