Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2505-9. doi: 10.1016/j.bmcl.2011.02.047. Epub 2011 Feb 21.

Abstract

This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC(50)) and was compared to the chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent π-π or π-cationic interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism
  • Ambenonium Chloride / chemistry
  • Ambenonium Chloride / pharmacology
  • Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / chemistry
  • Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / pharmacology
  • Binding Sites
  • Butyrylcholinesterase / chemistry*
  • Butyrylcholinesterase / genetics
  • Butyrylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use
  • Edrophonium / chemistry
  • Edrophonium / pharmacology
  • Humans
  • Kinetics
  • Molecular Dynamics Simulation
  • Myasthenia Gravis / drug therapy*
  • Protein Binding
  • Quinolinium Compounds / chemistry*
  • Quinolinium Compounds / pharmacology
  • Quinolinium Compounds / therapeutic use
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Quinolinium Compounds
  • Recombinant Proteins
  • Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide
  • Ambenonium Chloride
  • Edrophonium
  • Acetylcholinesterase
  • Butyrylcholinesterase