Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1815-9. doi: 10.1016/j.bmcl.2014.02.019. Epub 2014 Feb 15.

Abstract

Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.

Keywords: 1,3-Dipolar cycloaddition; AChE; Alzheimer’s disease; BChE; Molecular docking; Spiropyrrolidines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Cholinesterases / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship
  • Torpedo

Substances

  • Cholinesterase Inhibitors
  • Pyrrolidines
  • Spiro Compounds
  • Cholinesterases