Synthesis, Activity, and Molecular Modeling of New 2,4-Dioxo-5-(naphthylmethylene)-3-thiazolidineacetic Acids and 2-Thioxo Analogues as Potent Aldose Reductase Inhibitors

Abstract

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 ≅ 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.