SYNTHESIS, ACTIVITY, AND MOLECULAR MODELING OF NEW 4-DIOXO-5-(NAPHTHYLMETHYLENE)-3-THIAZOLIDINEACETIC ACIDS AND 2-THIOXO ANALOGS AS POTENT ALDOSE REDUCTASE INHIBITORS

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