Synthesis, integrated computational and experimental evaluation of coumarin-based α-amylase and α-glucosidase inhibitors for postprandial hyperglycemia

Based on the antidiabetic effects of simple natural coumarins, 14 simple coumarin scaffolds were synthesized and screened for α-glucosidase and α-amylase inhibitory activity to assess their postprandial hyperglycemic effects. Among them, the two carbohydrazide derivatives, 5 and 6 , exhibited remarkable inhibitory activities. Compound 5 exhibited an IC 50 value of 2.22 µg/mL against α-glucosidase, whereas compound 6 showed potent activity against α-amylase (IC 50 = 2.98 µg/mL), both outperforming the standard drug acarbose. The experimental finding was further supported by docking studies, which showed favourable binding interactions with the target enzyme. MD simulation of the α-glucosidase–compound 5 complex confirmed the structural stability and stable binding interactions throughout the 100 ns simulation period. MM-PBSA analysis also demonstrated a favourable binding free energy, supporting the strong affinity of compound 5 for one of the target receptors. In the OGTT (oral glucose tolerance test), both compounds also displayed potential glucose-lowering activity. The possible structure-activity (SAR) studies revealed that C-3 substitution and appropriate structural optimization at the 6th position on the coumarin moiety can lead to the development of novel small molecules for postprandial hyperglycemia.