Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship

Abstract

Abstract. Although multiple biochemical pathways are likely to be responsible for the pathogenesis of diabetic complications, substantial evidence suggests a key role for the polyol pathway and oxidative stress initiated by hyperglycemia. Thus aldose reductase, the first enzyme of the polyol pathway, has been identified as a potential target of pharmacological intervention to prevent diabetic complications. Aldose reductase inhibitors endowed with antioxidant activity would be dually beneficial. The aim of the study was to evaluate the structure-activity relationship of commercially available indole derivatives supported by the molecular modeling of their interaction with the enzyme aldose reductase from the viewpoint of the inhibitory effect on the enzyme and their antioxidant activity. The partially purified aldose reductase was prepared from rabbit eye lenses. In vitro inhibiton of the aldose reductase was determined by a conventional method. Antioxidant action of the compounds was documented in a DPPH test. Marked differences were recorded in the aldose reductase inhibition activities of 1-and 3-indole acetic acid derivatives. The interaction energies of the inhibitor vs. enzyme-NADP + complexes, calculated by computer aided molecular modeling, were in agreement with the higher inhibitory efficacy of 1-indole acetic acid in contrast with 3-indole acetic acid. The more efficient 1-indole acetic acid was proved to create stronger electrostatic interaction with NADP + . However, the order of the antioxidant activities of the compounds studied was not in agreement with that of the inhibitory efficacies.

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

“…The short term cultivations were preferred to avoid substantial permeability changes of the eye lenses. The washed lenses were kept deep-frozen for sorbitol determination which was performed as described before (Stefek et al, 2011). In brief, the frozen lenses were let to melt at the ambient temperature.…”

“…Substituted indole-1-acetic acids, structurally related to the above mentioned indole-based PPAR agonists, represent a group of ARIs of high activity and selectivity (Van Zandt et al, 2005;Luker et al, 2011;Juskova et al, 2011), with lidorestat as a lead. Yet lidorestat (Fig.…”

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

“…Despite the failure of lidorestat in clinical trials and based on encouraging highly efficient derivatives 3c – f , we still had believed that indol-1-yl acetic acid moiety was a promising starting fragment for drug design. Indeed, in our preliminary study [ 75 ], indol-1-yl acetic acid 4a was identified as an ARI with a mild efficacy. We decided to employ this compound as a starting structural moiety (hit) in a fragment based drug design.…”

“…On the other hand, in the case of the indol-3-yl acetic acid derivatives with unsubstituted nitrogen 4c , 4 d , the antiradical activity higher than that of the structurally related reference antioxidant melatonin was recorded. The electron donor substituent -OCH 3 in the more efficient derivative 4d facilitates the delocalization of the unpaired electron of the intermediate indolyl radical originating after free radical encounter [ 75 ].…”

Does Inhibition of Aldose Reductase Contribute to the Anti-Inflammatory Action of Setipiprant?

“…Setipiprant is a derivative of indole-1-acetic acid. Since compounds of this group are efficient inhibitors of aldose reductase (Van Zandt et al 2005, Van Zandt et al 2009, Juskova et al 2011 we were prompted to investigate the aldose reductase inhibitory activity of setipiprant. Considering the PgF2α synthase activity of aldose reductase isolated from the human placenta and mouse kidney (Kabututu et al 2009), and more importantly the recently reported PGD2 synthase activity of recombinant human aldose reductase (AKR1B1) and mouse aldo-keto reductase AKR1B3 (Nagata et al 2011), the aldose reductase inhibitory activity would be of great relevance for potential molecular mechanisms involved in biological action of setipiprant.…”