Novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties as cholinesterases inhibitors

Eur J Med Chem. 2010 Dec;45(12):5602-11. doi: 10.1016/j.ejmech.2010.09.010. Epub 2010 Sep 17.

Abstract

The study presents synthesis and biological activity of novel alkyl- and arylcarbamate derivatives with N-benzylpiperidine and N-benzylpiperazine moieties designed as cholinesterases inhibitors. These fragments turned out to determine compounds' selectivity between AChE and BuChE. Derivatives of N-benzylpiperazine (16-25) were selective BuChE inhibitors with 3-(2-(4-benzylpiperazin-1-yl)-2-oxoethyl)-phenyl butylcarbamate (22) being the most potent compound (pIC50=5.00) while a series of carbamate derivatives of N-benzylpiperidine (5-14) displayed non-selective BuChE/AChE inhibitory activity. Molecular modelling studies point out significant differences between orientations of these two groups of compounds in the active site of AChE, which can be an explanation of their different biological activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Butyrylcholinesterase / metabolism*
  • Carbamates / chemical synthesis
  • Carbamates / chemistry
  • Carbamates / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology*
  • Enzyme Activation / drug effects
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Piperazines / chemistry*
  • Piperidines / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Cholinesterase Inhibitors
  • N-benzylpiperazine
  • Piperazines
  • Piperidines
  • 1-benzylpiperidine
  • Acetylcholinesterase
  • Butyrylcholinesterase