Synthesis, anti-HCV, antioxidant, and peroxynitrite inhibitory activity of fused benzosuberone derivatives

Eur J Med Chem. 2010 Feb;45(2):492-500. doi: 10.1016/j.ejmech.2009.10.033. Epub 2009 Oct 29.

Abstract

Reaction of benzosuberone 1 with dimethylformamide-dimethylacetal (DMF-DMA) gives 2-dimethylamino-methylenebenozosuberone 2 which in turn reacts with heterocyclic amines to furnish new heterocyclic ring systems 6-9. Moreover, enaminone 2 reacts with hydrazine hydrate and hydroxylamine hydrochloride to afford the corresponding benzo[6,7]cyclohepta[1,2-c]pyrazole (10) and benzo[6,7]cyclohepta[2,1-d]isoxazole (12), respectively. In addition, the reactions of enaminone 2 with active methylene compounds afforded benzo[6,7]cyclohepta[1,2-b]pyridines (13-18). The X-ray crystallographic analysis of compounds 6 and 16, were recorded. We demonstrated the ability of nine new synthesized compounds to inhibit Hepatitis C Virus (HCV) and Subacute Sclerosing Panencephalitis (SSPE) due to structural similarity between ribavirin and some of the newly synthesized compounds were they contain triazoles and its bioisosters. In addition, the ability of ten synthesized compounds to react with the biologically relevant reactive nitrogen species, peroxynitrite was investigated indirectly by measurement of their ability to inhibit ONOO(-)-induced tyrosine nitration. The antioxidant activity of these ten compounds was also studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay.

MeSH terms

  • Animals
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Biphenyl Compounds / chemistry
  • Brain / drug effects
  • Brain / virology
  • Cricetinae
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Microbial Sensitivity Tests
  • Peroxynitrous Acid / antagonists & inhibitors*
  • Picrates / chemistry
  • Pyridines / chemistry
  • Replicon / drug effects
  • Viral Nonstructural Proteins / antagonists & inhibitors

Substances

  • Antioxidants
  • Antiviral Agents
  • Biphenyl Compounds
  • Heterocyclic Compounds, 2-Ring
  • NS3 protein, hepatitis C virus
  • Picrates
  • Pyridines
  • Viral Nonstructural Proteins
  • Peroxynitrous Acid
  • 1,1-diphenyl-2-picrylhydrazyl
  • pyridine