[Imidazolidine/thiazolidine-acetate aldose reductase inhibitors]. / Les inhibiteurs de l'aldose-réductase de structure imidazolidine/thiazolidine-acétique.

We studied a new family of aldose-reductase inhibitors with an imidazolidine arylmethylene and thiazolidine-acetate structure susceptible to prevent ocular, renal and vascular complications of insulin-dependent diabetes mellitus. We examined the role of the enzyme in the pathological processes involved and reviewed knowledge of known aldose reductase inhibitors leading to the development of the basic structure modulated to have insight into the different elements of the structure-quantitative activity relationship. Potential inhibitors are synthesized by condensation of heterocyclic rings and aldehyde aromatic rings. Their identity and structure were established by magnetic resonance spectroscopy (MRS) based on proton-carbon couplage constants and the homonuclear NOE effect. The structure-activity correlations were analyzed on the basis of the IC50 using a structural model and a physicAL model which showed the importance of the sulfur atom in the heterocyclic ring due to its important lipophilic contribution. Finally, a molecular modeling approach led to a provisional descriptive model of the inhibitor-enzyme interaction.

Synthesis, activity, and molecular modeling of new 2, 4-dioxo-5-(naphthylmethylene)-3-thiazolidineacetic acids and 2-thioxo analogues as potent aldose reductase inhibitors.

A series of 2,4-dioxo-5-(2-naphthylmethylene)-3-thiazolidineacetic acids and 2-thioxo analogues have been prepared as aldose reductase inhibitors. In vitro inhibitory activities of bovine lens aldose reductase were determined by a conventional method. 1-Naphthyl-substituted derivatives of the 2-thioxo series were the more potent inhibitors (IC50 congruent with 10 nM) with similar activity to that of Epalrestat. Structural analysis, especially by X-ray crystallography of two selected compounds, and molecular modeling comparisons with Zopolrestat were performed. These results provide explanations of the good activity of the inhibitor, the preference for 1-naphthyl-substituted compounds, and the nature of molecular interactions in these systems.