Synthesis and biological evaluation of 2'-oxo-2,3-dihydro-3'H- spiro[chromene-4,5'-[1,3]oxazolidin]-3'yl]acetic acid derivatives as aldose reductase inhibitors

Arch Pharm (Weinheim). 2011 Jun;344(6):372-85. doi: 10.1002/ardp.201000302. Epub 2011 Feb 14.

Abstract

Aldose reductase (ARL2) is the first enzyme in the polyol pathway which catalyzes the NADPH-dependent reduction of glucose to sorbitol. Its involvement on diabetic complications makes this enzyme a challenge therapeutic target widely investigated to limit and/or prevent them. On this basis, a limited series of 4-spiro-oxazolidinone-benzopyran derivatives (1-7) were synthesized to evaluate them as potential ARL2 inhibitors. The activity was determined spectrophotometrically by monitoring the oxidation of NADPH catalyzed by ALR2. Within the series of compounds, the 4-methoxy derivative 1b showed to be the most active compound, exhibiting inhibitory levels in the submicromolar range. In addition, the activity against the aldehyde reductase isoform (ARL1) was also evaluated. Unlike sorbinil (reference drug) that lack of selectivity towards the two enzyme all the tested compounds resulted to be devoid of ARL1 inhibitory activity (IC(50) > 10 µM), thus proving to be selective.

Publication types

  • Comparative Study

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Imidazolidines / pharmacology
  • Inhibitory Concentration 50
  • NADP / metabolism
  • Oxazolidinones / chemical synthesis
  • Oxazolidinones / chemistry
  • Oxazolidinones / pharmacology*
  • Oxidation-Reduction / drug effects
  • Spectrophotometry
  • Structure-Activity Relationship

Substances

  • Benzopyrans
  • Enzyme Inhibitors
  • Imidazolidines
  • Oxazolidinones
  • NADP
  • Aldehyde Reductase
  • sorbinil