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

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 PPARγ. 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 PPARγ, 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.

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

“…On the other hand, combination of –CHO and –COCH 3 substituents in position 3 with methyl in position 2 for compounds 4k and 4l, respectively, resulted in marked increase in inhibition efficacy as documented by substantial decrease of IC 50 values (23- to 35-fold, respectively) in comparison with unsubstituted indol-1-yl acetic acid ( 4a ) [ 71 ]. In compound 4m , the presence of benzyloxy group in position 5 resulted in about 10-fold improvement of inhibition when compared with the unsubstituted indol-1-yl acetic acid ( 4a ), based on the experimental IC 50 values [ 77 ].…”