Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents

Bioorg Med Chem. 2016 Feb 15;24(4):712-20. doi: 10.1016/j.bmc.2015.12.040. Epub 2015 Dec 24.

Abstract

A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.

Keywords: Heterocyclization; Isoxazole; Lipoxygenase; Mitochondria; Reduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimycin A / pharmacology
  • Biphenyl Compounds / antagonists & inhibitors
  • Brain / cytology
  • Brain / drug effects
  • Brain / enzymology
  • Cell Line, Tumor
  • Free Radical Scavengers / chemical synthesis*
  • Free Radical Scavengers / pharmacology
  • Glycine max / chemistry
  • Glycine max / enzymology
  • Humans
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / pharmacology
  • Lipid Peroxidation / drug effects
  • Lipoxygenase / metabolism*
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / pharmacology
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / drug effects*
  • Mitochondria / enzymology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / enzymology
  • Oligomycins / pharmacology
  • Picrates / antagonists & inhibitors
  • Primary Cell Culture
  • Rats
  • Structure-Activity Relationship

Substances

  • Biphenyl Compounds
  • Free Radical Scavengers
  • Isoxazoles
  • Lipoxygenase Inhibitors
  • Oligomycins
  • Picrates
  • Antimycin A
  • 1,1-diphenyl-2-picrylhydrazyl
  • Lipoxygenase