Synthesis and structure-activity relationship study of tacrine-based pyrano[2,3-c]pyrazoles targeting AChE/BuChE and 15-LOX

Eur J Med Chem. 2016 Nov 10:123:298-308. doi: 10.1016/j.ejmech.2016.07.043. Epub 2016 Jul 21.

Abstract

A series of tacrine-based pyrazolo[4',3':5,6]pyrano[2,3-b]quinolines and related compounds were designed and synthesized for targeting AChE, BuChE and 15-LOX enzymes in the field of Alzheimer's disease therapy. Most of compounds showed potent activity against cholinesterases and mild potency toward 15-LOX enzyme. In particular, compounds 29, 32 and 40 displayed inhibition at nano-molar level against AChE and BuChE (IC50s = 0.005-0.08 μM), being more potent than reference drug tacrine. Moreover, compound 32 with IC50 value of 31 μM was the most potent compound against 15-LOX. The cytotoxicity assay on HepG2 cells revealed that compounds 29 and 32 showed no significant cytotoxic activity even at concentration of 50 μM. The cytotoxicity of compounds 29 and 32 was significantly less than that of tacrine at higher concentrations.

Keywords: 15-Lipoxygenase; Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Tacrine.

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Arachidonate 15-Lipoxygenase / metabolism
  • Blood-Brain Barrier / metabolism
  • Butyrylcholinesterase / metabolism*
  • Cell Survival / drug effects
  • Chemistry Techniques, Synthetic
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology*
  • Hep G2 Cells
  • Humans
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / metabolism
  • Lipoxygenase Inhibitors / pharmacology
  • Molecular Docking Simulation
  • Protein Conformation
  • Pyrazoles / chemistry*
  • Structure-Activity Relationship
  • Tacrine / chemical synthesis
  • Tacrine / chemistry*
  • Tacrine / metabolism
  • Tacrine / pharmacology*

Substances

  • Cholinesterase Inhibitors
  • Lipoxygenase Inhibitors
  • Pyrazoles
  • Tacrine
  • Arachidonate 15-Lipoxygenase
  • Acetylcholinesterase
  • Butyrylcholinesterase