[5-(Benzyloxy)-1H-indol-1-yl]acetic acid, an aldose reductase inhibitor and PPAR gamma ligand


Prnova M. S., Majekova M., Milackova I., Diez-Dacal B., Perez-Sala D., Ceyhan M. Ş., ...More

ACTA BIOCHIMICA POLONICA, vol.62, no.3, pp.523-528, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 62 Issue: 3
  • Publication Date: 2015
  • Doi Number: 10.18388/abp.2014_953
  • Journal Name: ACTA BIOCHIMICA POLONICA
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.523-528
  • Keywords: aldose reductase inhibitor, PPAR. ligand, diabetes, indole, ACTIVATED RECEPTOR AGONISTS, SELECTIVE INHIBITORS, ALDEHYDE REDUCTASE, STRUCTURAL BIOLOGY, HIGHLY POTENT, DISCOVERY, DESIGN, ANTIOXIDANTS, MECHANISM, MODELS
  • Gazi University Affiliated: No

Abstract

Based on overlapping structural requirements for both efficient aldose reductase inhibitors and PPAR ligands, [5-(benzyloxy)-1H-indol-1-yl] acetic acid (compound 1) was assessed for inhibition of aldose reductase and ability to interfere with PPAR gamma. Aldose reductase inhibition by 1 was characterized by IC50 in submicromolar and low micromolar range, for rat and human enzyme, respectively. Selectivity in relation to the closely related rat kidney aldehyde reductase was characterized by approx. factor 50. At organ level in isolated rat lenses, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner. To identify crucial interactions within the enzyme binding site, molecular docking simulations were performed. Based on luciferase reporter assays, compound 1 was found to act as a ligand for PPAR gamma, yet with rather low activity. On balance, compound 1 is suggested as a promising lead-like scaffold for agents with the potential to interfere with multiple targets in diabetes.