Imidazo[1,2-a]quinoxalines: synthesis and cyclic nucleotide phosphodiesterase inhibitory activity

Eur J Med Chem. 2001 Mar;36(3):255-64. doi: 10.1016/s0223-5234(01)01213-2.

Abstract

A group of imidazo[1,2-a]quinoxalines have been synthesised from quinoxaline by condensation of an appropriate haloester or intramolecular cyclisation of a keto moiety on an intracyclic nitrogen atom. The reactivity of the heterocycle was explored through diverse reactions such as electrophilic substitution, lithiation and halogen-metal exchange to give access to a new series of derivatives. Confirmation of their structure was mainly performed by NMR, after careful assignment of the signals in comparison to previous attributions made on the parent imidazo[1,2-a]quinoxaline and discussion of available data in the literature. The cyclic nucleotide phosphodiesterase inhibitor activity of some of these derivatives has been assessed on isoenzymes type III and type lV. Compound 15, 4-(methylamino)imidazo[1,2-a]quinoxaline-2-carbonitrile, exhibited potent relaxant activity on smooth muscle, with a potency similar to the one measured with SCA 40, its structural analogue in the imidazo[1,2-a]pyrazine series.

MeSH terms

  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Cardiotonic Agents / pharmacology
  • Cattle
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Guinea Pigs
  • Inhibitory Concentration 50
  • Isoenzymes / antagonists & inhibitors
  • Magnetic Resonance Spectroscopy
  • Male
  • Muscle Relaxation / drug effects
  • Muscle, Smooth / drug effects
  • Nitriles / chemical synthesis
  • Nitriles / chemistry
  • Nitriles / pharmacology*
  • Pyrazines / pharmacology
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / chemistry*
  • Quinoxalines / pharmacology*
  • Structure-Activity Relationship

Substances

  • 4-(methylamino)imidazo(1,2-a)quinoxaline-2-carbonitrile
  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Isoenzymes
  • Nitriles
  • Pyrazines
  • Quinoxalines
  • 5-(4-acetamidophenyl)pyrazin-2(1H)-one
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases