ABSTRACT
In search of dually active PPAR-modulators/aldose reductase (ALR2) inhibitors, 16 benzylidene thiazolidinedione derivatives, previously reported as partial PPARγ agonists, together with additional 18 structural congeners, were studied for aldose reductase inhibitory activity. While no compounds had dual property, our efforts led to the identification of promising inhibitors of ALR2. Eight compounds (11, 15-16, 20-24, 30) from the library of 33 compounds were identified as potent and selective inhibitors of ALR2. Compound 21 was the most effective and selective inhibitor with an IC50 value of 0.95 ± 0.11 and 13.52 ± 0.81 µM against ALR2 and aldehyde reductase (ALR1) enzymes, respectively. Molecular docking and dynamics studies were performed to understand inhibitor-enzyme interactions at the molecular level that determine the potency and selectivity. Compound 21 was further subjected to in silico and in vitro studies to evaluate the pharmacokinetic profile. Being less acidic (pKa = 9.8), the compound might have a superior plasma membrane permeability and reach the cytosolic ALR2. This fact together with excellent drug-likeness criteria points to improved bioavailability compared to the clinically used compound Epalrestat. The designed compounds represent a novel group of non-carboxylate inhibitors of aldose reductase with an improved physicochemical profile.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Thiazolidinediones/pharmacology , Aldehyde Reductase/chemistry , Aldehyde Reductase/metabolism , Animals , Caco-2 Cells , Catalytic Domain , Dogs , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Madin Darby Canine Kidney Cells , Male , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Rats, Wistar , Structure-Activity Relationship , Thiazolidinediones/chemical synthesis , Thiazolidinediones/metabolism , Thiazolidinediones/pharmacokineticsABSTRACT
(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids exhibit a wide range of pharmacological activities. Among them, the only derivative used in clinical practice is the aldose reductase inhibitor epalrestat. Structurally related compounds, [(5Z)-(5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)]acetic acid derivatives were prepared previously as potential antifungal agents. This study was aimed at the determination of aldose reductase inhibitory action of the compounds in comparison with epalrestat and evaluation of structure-activity relationships (SAR). The aldose reductase (ALR2) enzyme was isolated from the rat eye lenses, while aldehyde reductase (ALR1) was obtained from the kidneys. The compounds studied were found to be potent inhibitors of ALR2 with submicromolar IC50 values. (Z)-2-(5-(1-(5-butylpyrazin-2-yl)ethylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (3) was identified as the most efficacious inhibitor (over five times more potent than epalrestat) with mixed-type inhibition. All the compounds also exhibited low antiproliferative (cytotoxic) activity to the HepG2 cell line. Molecular docking simulations of 3 into the binding site of the aldose reductase enzyme identified His110, Trp111, Tyr48, and Leu300 as the crucial interaction counterparts responsible for the high-affinity binding. The selectivity factor for 3 in relation to the structurally related ALR1 was comparable to that for epalrestat. SAR conclusions suggest possible modifications to improve further inhibition efficacy, selectivity, and biological availability in the group of rhodanine carboxylic acids.
