Novel Derivatives of Rhodanine-3-Hippuric Acid as Active Inhibitors of Aldose Reductase: Synthesis, Biological Evaluation, and Molecular Docking Analysis

Abstract

Inhibitors of aldose reductase provide a feasible mode of action against diabetic complications. Based on the marketed aldose reductase inhibitor epalrestat containing rhodanine nucleus, rhodanine-3-hippuric acid and its 5-arylidene derivatives were synthesized. The structure of newly synthesized compounds was confirmed by IR, ¹H NMR, and ¹³C NMR spectrometry. In vitro aldose reductase inhibitory activity of the synthesized compounds was assayed and the results showed that most of the derivatives were potent against aldose reductase with IC₅₀ values ranging from 0.2 to 2.36 µM. Two of the compounds with the highest efficacies among the tested compounds (IC₅₀ values of 0.2 and 0.6 µM) were more potent than epalrestat. Molecular docking studies were undertaken to explore the binding modes of all compounds into the active site of aldose reductase in order to rationalize the inhibitory efficacy of these derivatives. Rhodanine-3-hippuric acid and all its arylidene derivatives fulfil Lipinski’s rule and show good drug-likeness property. In conclusion, novel compounds synthesized in the present study have proved to be potential drugs for diabetic complications.