NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3162-5. doi: 10.1016/j.bmcl.2013.04.008. Epub 2013 Apr 10.

Abstract

To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Binding Sites
  • Butyrylcholinesterase / chemistry*
  • Butyrylcholinesterase / metabolism
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism
  • Flurbiprofen / analogs & derivatives*
  • Flurbiprofen / chemical synthesis
  • Flurbiprofen / chemistry
  • Flurbiprofen / metabolism
  • Kinetics
  • Nitrates / chemical synthesis
  • Nitrates / chemistry*
  • Nitrates / metabolism
  • Nitric Oxide / metabolism*
  • Protein Binding
  • Structure-Activity Relationship
  • Tacrine / analogs & derivatives*
  • Tacrine / chemical synthesis
  • Tacrine / chemistry
  • Tacrine / metabolism
  • Vasodilator Agents / chemical synthesis
  • Vasodilator Agents / chemistry*
  • Vasodilator Agents / metabolism

Substances

  • Cholinesterase Inhibitors
  • Nitrates
  • Vasodilator Agents
  • Nitric Oxide
  • Tacrine
  • Flurbiprofen
  • Acetylcholinesterase
  • Butyrylcholinesterase