Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1 H- Benzimidazole Analogues

Biomolecules. 2019 Dec 12;9(12):870. doi: 10.3390/biom9120870.

Abstract

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman's spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC₅₀ 80-90 nM) AChE and moderate (IC₅₀ 5-0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure-activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

Keywords: SAR; acetylcholinesterase; benzimidazole; beta amyloid; butyrylcholinesterase; inhibitor; lipophilicity; molecular docking.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Biphenyl Compounds / antagonists & inhibitors
  • Butyrylcholinesterase / metabolism*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Horses
  • Humans
  • Kinetics
  • Molecular Docking Simulation*
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Picrates / antagonists & inhibitors
  • Protein Aggregates / drug effects
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Benzimidazoles
  • Biphenyl Compounds
  • Cholinesterase Inhibitors
  • Peptide Fragments
  • Picrates
  • Protein Aggregates
  • amyloid beta-protein (1-42)
  • 1,1-diphenyl-2-picrylhydrazyl
  • Acetylcholinesterase
  • Butyrylcholinesterase