Benzoselenazolinone derivatives designed to be glutathione peroxidase mimetics feature inhibition of cyclooxygenase/5-lipoxygenase pathways and anti-inflammatory activity

J Med Chem. 1994 Sep 2;37(18):2903-11. doi: 10.1021/jm00044a011.

Abstract

Two series of compounds, substituted benzoselenazolinones and their opened analogs, diselenides, were prepared. The diselenides were designed according to the available SAR about glutathione peroxidase mimics and were expected to have activity. An initial series of tests was performed in order to assess the glutathione peroxidase and antioxidant activity of the diselenides compared to their cyclized analogs. The diselenides were shown to be very potent (up to 3 times the activity of ebselen), whereas the benzoselenazolinones were inactive, thus confirming our hypothesis. A second series of tests was done to determine the anti-inflammatory potency of the two series. Both were found to be potent on cyclooxygenase and 5-lipoxygenase pathways (up to 95% inhibition at 10(-5) M). Some compounds were selective, and the variations in the activity allowed us to draft some structure-activity relationships. The most interesting compound of each series, 6-benzoylbenzoselenazolinone and bis[(2-amino-5-benzoyl)phenyl] diselenide, was tested in vivo on the rat foot edema induced with different phlogistic agents and was shown to have some anti-inflammatory properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antioxidants / chemical synthesis
  • Antioxidants / pharmacology
  • Azoles / chemical synthesis*
  • Azoles / pharmacology*
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / pharmacology
  • Glutathione Peroxidase / metabolism*
  • Hemolysis / drug effects
  • Humans
  • In Vitro Techniques
  • Isoindoles
  • Lipid Peroxidation / drug effects
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / pharmacology
  • Male
  • Organoselenium Compounds / chemical synthesis*
  • Organoselenium Compounds / pharmacology*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Azoles
  • Cyclooxygenase Inhibitors
  • Isoindoles
  • Lipoxygenase Inhibitors
  • Organoselenium Compounds
  • ebselen
  • Glutathione Peroxidase