Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer's disease

Bioorg Med Chem. 2021 Apr 1:35:116074. doi: 10.1016/j.bmc.2021.116074. Epub 2021 Feb 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antioxidants
  • Benzofurans / chemical synthesis
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Benzylidene Compounds / chemical synthesis
  • Benzylidene Compounds / chemistry
  • Benzylidene Compounds / pharmacology*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Copper / pharmacology
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Female
  • Humans
  • Male
  • Mannich Bases / chemical synthesis
  • Mannich Bases / chemistry
  • Mannich Bases / pharmacology
  • Mice
  • Mice, Inbred Strains
  • Models, Molecular
  • Molecular Structure
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • PC12 Cells
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Protein Aggregates / drug effects
  • Rats
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Benzofurans
  • Benzylidene Compounds
  • Cholinesterase Inhibitors
  • Mannich Bases
  • Neuroprotective Agents
  • Peptide Fragments
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • Copper
  • phthalide
  • Acetylcholinesterase
  • Butyrylcholinesterase