Coumarin-Based Thiosemicarbazones: Molecular Docking, ADMET Analysis, Synthesis, and α-Glucosidase Inhibition

Diabetes mellitus (DM) is a chronic disease caused by improper insulin secretion or insulin resistance, leading to postprandial hyperglycemia. α-Glucosidase is the most effective target for treating hyperglycemia, as it breaks down carbohydrates into glucose in the gastrointestinal tract. Coumarin scaffolds exhibit a wide range of biological activities such as anti-diabetic, anti-cancer, anti-viral, anti-bacterial, and anti-coagulant etc. The primary objectives of this study were to explore the effectiveness of novel coumarin scaffolds as potent α-glucosidase inhibitors. A novel series of fifteen coumarin-based thiosemicarbazones (7a–7o) was initially screened against α-glucosidase (PDB ID: 3A4A) through molecular docking and ADMET analysis. Among them, four lead candidates (7a–7d) with the highest binding scores (–10.5 to –11.0 kcal/mol) as compared to the reference drug acarbose (–9.6 kcal/mol), and favorable physicochemical and pharmacokinetic properties, were synthesized. These candidates also exhibited excellent in vitro α-glucosidase inhibitory activity with IC50 values ranging from 19.15 ± 0.14 to 31.23 ± 0.20 µM. The IC50 value of the reference drug (acarbose) was observed to be 56.37 ± 1.32 µM.