Thiazolidinedione-based dual inhibitors of α-amylase and aldose reductase: Design, in vitro evaluation, and in vivo hypoglycemic activity

This study reports the design, synthesis, and biological evaluation of thiazolidinedione (TZD) derivatives as dual inhibitors of α-amylase (α-AMY) and aldose reductase (AR) for potential use in the management of diabetes mellitus. Using a structure-based design strategy, the epalrestat scaffold was modified by introducing a TZD core with either an N-ethyl urea or N-acetamide linker and various benzylidene substituents. Two series of compounds (8a-g and 9a-g) were synthesized and characterized. In vitro assays showed that several derivatives exhibited dual inhibitory activity. Compound 9a, containing an N-acetamide linker and a 4-fluorobenzylidene group, inhibited AR (IC₅₀ = 117.6 nM) and α-AMY (IC₅₀ = 2.2 μM), with lower IC₅₀ values than epalrestat (127 nM) and acarbose (15 μM), respectively. Structure-activity relationship analysis indicated that the N-acetamide linker favored AR inhibition, whereas the N-ethyl urea linker was more favorable for α-AMY inhibition. Kinetic studies showed that 9a inhibits AR non-competitively and α-AMY via a mixed-type mechanism. Molecular docking suggested that 9a binds to an allosteric site in AR and the catalytic pocket of α-AMY. In a streptozotocin-induced diabetic mouse model, 9a reduced blood glucose levels by 68.4% at a dose of 50 mg/kg. These results suggest that 9a could serve as a starting point for further development of multi-target antidiabetic agents.