Investigation of potent inhibitors of cholinesterase based on thiourea and pyrazoline derivatives: Synthesis, inhibition assay and molecular modeling studies

Bioorg Chem. 2019 Sep:90:103036. doi: 10.1016/j.bioorg.2019.103036. Epub 2019 Jun 4.

Abstract

Owing to the desperate need of new drugs development to treat Alzheimer's ailment the synthesis of 1-aroyl-3-(5-(4-chlorophenyl)-1,2,4-triazole-3-thioneaminylthioureas (2-6) starting from (4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazole-3-thiol) (1) and synthesis of 1-(3-(4-aminophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-isobutylphenyl)propan-1-one (7-9) starting from 2-(4-isobutylphenyl)propanehydrazide (a) with the cyclization with substituted chalcones (c-e) was carried out. To check the biological potential of the synthesized compounds, all were subjected to acetylcholinesterase (AChE) and butrylcholinesterase (BChE) inhibition assays. The most potent and selective inhibitor for the acetylcholinesterase was compound 7 having an inhibitory concentration of 123 ± 51 nM, whereas, compound 6 was found as selective inhibitor of butyrylcholinesterase (BChE) with an IC50 value of 201 ± 80 nM. However, the compounds 1 and 2 were found as dual inhibitors i.e. active against both acetylcholinesterase as well as butyrylcholinesterase.

Keywords: Alzheimer disease; Chalcones; Enzyme inhibition; Ibuprofen; Pyrazolines; Triazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Animals
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism
  • Catalytic Domain
  • Cell Proliferation / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / pharmacology*
  • HeLa Cells
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology*
  • Torpedo

Substances

  • Cholinesterase Inhibitors
  • Pyrazoles
  • Acetylcholinesterase
  • Butyrylcholinesterase
  • Thiourea