Abstract
To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10-5 and 6.16 × 10-4 μM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency, disaggregation ability on Aβ1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.
Keywords:
3-benzylidene/benzylphthalide Mannich base derivatives; AChE inhibitors; Alzheimer’s disease; Antioxidants; MAO-B inhibitors; Multifunctional anti-AD agents.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / metabolism
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / metabolism
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Animals
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Antioxidants
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Benzofurans / chemical synthesis
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Benzofurans / chemistry
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Benzofurans / pharmacology*
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Benzylidene Compounds / chemical synthesis
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Benzylidene Compounds / chemistry
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Benzylidene Compounds / pharmacology*
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Butyrylcholinesterase / metabolism
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Cholinesterase Inhibitors / chemical synthesis
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / pharmacology*
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Copper / pharmacology
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Dose-Response Relationship, Drug
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Electrophorus
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Female
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Humans
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Male
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Mannich Bases / chemical synthesis
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Mannich Bases / chemistry
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Mannich Bases / pharmacology
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Mice
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Mice, Inbred Strains
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Models, Molecular
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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PC12 Cells
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / metabolism
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Protein Aggregates / drug effects
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Rats
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Structure-Activity Relationship
Substances
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Amyloid beta-Peptides
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Antioxidants
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Benzofurans
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Benzylidene Compounds
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Cholinesterase Inhibitors
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Mannich Bases
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Neuroprotective Agents
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Peptide Fragments
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Protein Aggregates
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amyloid beta-protein (1-42)
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Copper
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phthalide
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Acetylcholinesterase
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Butyrylcholinesterase