C-5-Arylidene-Thiazolidine-2,4-Dione Analogs Against Aldose Reductase: Design, Synthesis, Biological Evaluation, and...

Diabetic complications are major health problems that happen to people with diabetes when their blood sugar levels stay high for a long time and damage various body organs and systems. Inhibition of aldose reductase has emerged as a promising strategy for drug development and the management of diabetes-associated complications. In the research article, a novel series of 12 compounds, "C-5-arylidene thiazolidine-2,4-dione derivatives" was constructed, synthesized, and characterized using both spectral and non-spectral techniques. The confirmed synthesized compounds were subsequently screened for in vitro aldose reductase inhibitory activity. Among them, compounds 9h and 9a exhibited superior potency against aldose reductase protein with IC₅₀ values of 0.98 and 1.05 µM, respectively, as compared with the reference drug epalrestat (IC₅₀ value of 1.20 µM). Additionally, compounds 9l and 9i showed moderate aldose reductase inhibitory activity with an IC₅₀ value of 1.36 and 2.47 µM, respectively. Furthermore, the top four best active compounds were selected for in vivo anti-hyperglycaemic activity. Results revealed that all the tested compounds significantly decreased blood glucose levels at all time intervals. Computational analysis revealed that all synthesized candidates bound firmly in the protein cavity of aldose reductase via hydrogen bonds and steric interaction with the range of docking score -10.21 to -11.81 kcal/mol. Predicted in silico toxicity data suggested that the synthesized compounds were inactive and nontoxic against peroxisome proliferator-activated receptor-γ protein. These finding results support the potential of thiazolidine-2,4-dione derivatives as promising AR inhibitors for managing diabetic complications.