Mechanochemical Synthesis and Structure–Activity Relationships of Coumarin Derivatives in Antidiabetic Drug Discovery: Recent Advances in Green Medicinal Chemistry

ABSTRACTCoumarin derivatives represent versatile heterocyclic scaffolds with potential antidiabetic activity, particularlythrough inhibition of carbohydrate-hydrolyzing enzymes. This review evaluates recent advances in themechanochemical synthesis of coumarin derivatives and summarizes their structure–activity relationships(SAR) relevant to antidiabetic drug discovery.Literature published primarily between 2015 and 2026 wasreviewed using databases and literature sources including PubMed, Google Scholar, and relevant scientificliterature. Particular emphasis was placed on mechanochemical approaches, including ball milling, grindingassisted synthesis, liquid-assisted grinding, solvent-free synthesis, catalyst-assisted mechanochemistry,nanocatalyst-assisted mechanochemistry, mechanochemical Knoevenagel condensation, and continuousmechanochemical processing. Recent SAR, enzyme inhibition, molecular docking, ADMET, and computationalstudies were also evaluated.Mechanochemical approaches provide sustainable alternatives to conventionalsolution-phase synthesis by reducing solvent consumption, reaction time, energy requirements, and wastegeneration. Recent coumarin derivatives containing hydroxyl, methoxy, halogen, nitro, hydrazone, chalcone,benzimidazole, and oxazole substituents demonstrated promising inhibitory activity against α-amylase and α-glucosidase. Molecular docking and computational studies further supported favorable interactions and druglike properties of several derivatives.Integration of mechanochemical synthesis with SAR-guided optimizationand computational drug design provides a promising green strategy for the development of novel coumarinbased antidiabetic agents. Further experimental and clinical investigations are required to establish theirtherapeutic potential.