2,4-thiazolidinediones as dual-target inhibitors against carbohydrate metabolism enzymes in type 2 diabetes

The increasing prevalence of type 2 diabetes mellitus necessitates effective strategies targeting postprandial glucose dysregulation. Inhibition of α-amylase and α-glucosidase represents a validated therapeutic approach to limit carbohydrate digestion and glucose absorption. In this study, twenty-one 2,4-thiazolidinedione (TZD)-based derivatives, 5AT (a-g) and 5IT (a-n), were synthesised and evaluated using in silico and in vitro enzyme inhibition analyses. Molecular docking revealed strong binding affinities toward α-glucosidase (-7.1 to -9.7 kcal/mol) and α-amylase (-8.5 to -10.7 kcal/mol), supported by acceptable ADME and drug-likeness properties. Among the compounds, 5IT(b) displayed the most potent α-amylase inhibition (IC₅₀ value = 6.7 ± 0.2 μM), surpassing the reference drug acarbose (IC₅₀ = 27.30 ± 0.1 μM), and exhibited mixed-type inhibition with K_i and K_is values of 50.9 and 26.33 μM, respectively. The methoxy-substituted indole derivative 5IT(e) emerged as the strongest α-glucosidase inhibitor, with an IC₅₀ of 10.89 ± 1.8 μM, and followed a competitive inhibition mechanism with a K_i value of 18.8 μM. Based on the in vitro assays, compounds 5IT(a), 5IT(b), 5IT(e), 5IT(f), 5IT(h), 5IT(i), 5IT(j), 5IT(l), and 5IT(m) demonstrated dual inhibitory activity since these compounds effectively inhibited both Enzymes. Furthermore, the most potent compounds showed favourable cell viability. These results suggest that thiazolidinedione derivatives are promising dual α-amylase and α-glucosidase inhibitors for the development of antidiabetic therapies.