Preparation, in vitro evaluation and molecular modelling of pyridinium-quinolinium/isoquinolinium non-symmetrical bisquaternary cholinesterase inhibitors

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6663-6. doi: 10.1016/j.bmcl.2013.10.043. Epub 2013 Oct 31.

Abstract

Two series of non-symmetrical bisquaternary pyridinium-quinolinium and pyridinium-isoquinolinium compounds were prepared as molecules potentially applicable in myasthenia gravis treatment. Their inhibitory ability towards human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase was determined and the results were compared to the known effective inhibitors such as ambenonium dichloride, edrophonium bromide and experimental compound BW284C51. Two compounds, 1-(10-(pyridinium-1-yl)decyl)quinolinium dibromide and 1-(12-(pyridinium-1-yl)dodecyl)quinolinium dibromide, showed very promising affinity for acetylcholinesterase with their IC50 values reaching nM inhibition of acetylcholinesterase. These most active compounds also showed satisfactory selectivity towards acetylcholinesterase and they seem to be very promising as leading structures for further modifications and optimization. Two of the most promising compounds were examined in the molecular modelling study in order to find the possible interactions between the ligand and tested enzyme.

Keywords: Cholinesterase; In vitro; Inhibitor; Molecular modelling; Myasthenia gravis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / genetics
  • Acetylcholinesterase / metabolism*
  • 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 / metabolism
  • 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 / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology*
  • Enzyme Activation / drug effects
  • Humans
  • Models, Molecular*
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyridinium Compounds / chemistry*
  • Pyridinium Compounds / pharmacology
  • Quinolinium Compounds / chemistry*
  • Quinolinium Compounds / pharmacology
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Structure-Activity Relationship

Substances

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