New tacrine-derived AChE/BuChE inhibitors: Synthesis and biological evaluation of 5-amino-2-phenyl-4H-pyrano[2,3-b]quinoline-3-carboxylates

Eur J Med Chem. 2017 Mar 10:128:237-246. doi: 10.1016/j.ejmech.2017.01.042. Epub 2017 Feb 1.

Abstract

A series of poly-functionalized tacrine-derived compounds namely 5-amino-2-phenyl-4H-pyrano[2,3-b]quinoline-3-carboxylates were designed and synthesized as cholinesterases inhibitors. The in vitro inhibition assay against AChE and BuChE demonstrated that most of compounds had potent AChE inhibitory with reserving potential of BuChE inhibition. Among them, compound 6i bearing a 4-(3-bromophenyl) moiety showed the most potent activity against AChE/BuChE (IC50s values of 0.069 and 1.35 μM, respectively). The anti-AChE activity of 6i was five times more than that of tacrine. The SAR study revealed that chloro/bromo substituent at ortho or meta position of the 4-phenyl ring can improve the anticholinesterase activity.

Keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Tacrine.

Publication types

  • Evaluation Study

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Animals
  • Butyrylcholinesterase / chemistry*
  • Cell Proliferation / drug effects*
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology*
  • Hep G2 Cells
  • Humans
  • Molecular Docking Simulation
  • PC12 Cells
  • Pyrans / chemical synthesis*
  • Pyrans / pharmacology*
  • Quinolines / chemical synthesis*
  • Quinolines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tacrine / chemistry*

Substances

  • Cholinesterase Inhibitors
  • Pyrans
  • Quinolines
  • ethyl 5-amino-4-(3-bromophenyl)-2-phenyl-6,7,8,9-tetrahydro-4H-pyrano(2,3-b)quinoline-3-carboxylate
  • Tacrine
  • Acetylcholinesterase
  • Butyrylcholinesterase