Thiazolidinedione-triazole hybrids: design, synthesis, and biological evaluation as dual inhibitors of α-amylase and aldose reductase with antioxidant activity for antidiabetic therapy.

Simultaneous targeting of multiple pathogenic pathways implicated in hyperglycemia and diabetic complications represents a promising therapeutic strategy for managing diabetes mellitus. Herein, we report the design, synthesis, and biological evaluation of a novel series of thiazolidinedione-triazole hybrid derivatives 9a-o as multi-target antidiabetic agents. The target compounds were synthesized through a convergent N-alkylation of 5-arylidene-thiazolidine-2,4-dione potassium salts with α-bromo ketone intermediates bearing a 1,2,3-triazole motif, and their structures were confirmed by ¹H NMR, ¹³C NMR, and elemental analysis. In vitro evaluation revealed potent dual inhibitory activity against α-amylase (α-AMY) and aldose reductase (AR) for several derivatives. Compound 9a emerged as the most promising candidate, with AR inhibition (IC₅₀ = 0.074 µM) surpassing epalrestat (IC₅₀ = 0.107 µM) and α-AMY inhibition (IC₅₀ = 14.57 µM) exceeding acarbose (IC₅₀ = 18.24 µM). Similarly, compound 9j demonstrated exceptional dual potency (AR IC₅₀ = 0.092 µM; α-AMY IC₅₀ = 19.36 µM). DPPH radical scavenging assessment further revealed significant antioxidant activity for the lead compounds, with 9a (IC₅₀ = 42.28 µM) and 9j (IC₅₀ = 56.71 µM) approaching the potency of ascorbic acid (IC₅₀ = 38.49 µM). In vivo evaluation of 9a in a streptozotocin-induced diabetic mouse model demonstrated a significant dose-dependent hypoglycemic effect, reducing blood glucose levels by approximately 44.6% relative to the diabetic control at 50 mg/kg after six weeks of oral treatment. Molecular docking studies provided mechanistic insights into the binding interactions that govern the observed inhibitory activities. Collectively, these results establish 9a and 9j as promising multi-target lead candidates for the further development of antidiabetic therapeutics that simultaneously address hyperglycemia, diabetic complications, and oxidative stress.