Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer's agents

Bioorg Chem. 2019 Mar:83:559-568. doi: 10.1016/j.bioorg.2018.11.010. Epub 2018 Nov 13.

Abstract

A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2-aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N-benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Aβ self-aggregation as well as AChE-induced Aβ aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer's disease.

Keywords: AChE; Alzheimer's disease; Aβ aggregation; Benzothiazole; Neuroprotection; Pyridinium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / drug effects
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Butyrylcholinesterase / metabolism
  • Cell Line, Tumor
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / toxicity
  • Drug Design
  • Electrophorus
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / metabolism
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Heterocyclic Compounds, 2-Ring / toxicity
  • Horses
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Kinetics
  • Molecular Docking Simulation
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / toxicity
  • Oxidative Stress / drug effects
  • Peptide Fragments / drug effects
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Multimerization / drug effects
  • Pyridinium Compounds / chemical synthesis
  • Pyridinium Compounds / metabolism
  • Pyridinium Compounds / pharmacology*
  • Pyridinium Compounds / toxicity
  • Rats
  • Torpedo

Substances

  • Amyloid beta-Peptides
  • Cholinesterase Inhibitors
  • Heterocyclic Compounds, 2-Ring
  • Neuroprotective Agents
  • Peptide Fragments
  • Pyridinium Compounds
  • amyloid beta-protein (1-42)
  • Hydrogen Peroxide
  • Acetylcholinesterase
  • Butyrylcholinesterase