Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase

Bioorg Med Chem. 2014 Sep 1;22(17):5020-34. doi: 10.1016/j.bmc.2014.06.010. Epub 2014 Jun 26.

Abstract

A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure-activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines-N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation.

Keywords: Acyl guanidines; Alzheimer’s disease; Cholinesterase inhibitors; Neuroprotection; Pseudoirreversible inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Butyrylcholinesterase / blood
  • Butyrylcholinesterase / metabolism*
  • Carbamates / chemistry*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Electrophorus
  • Guanidines / chemical synthesis
  • Guanidines / chemistry
  • Guanidines / pharmacology*
  • Horses
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Cholinesterase Inhibitors
  • Guanidines
  • Acetylcholinesterase
  • Butyrylcholinesterase