Sustainable Mechanochemical Synthesis of Spiro[indoline‐pyrano[3,2‐ c ]pyran] Derivatives: Mechanistic Insights, Molecular Docking, and Antidiabetic Evaluation

ABSTRACT An efficient and eco‐benign liquid‐assisted mechanistic approach for synthesis of spiro[indoline‐3,4'‐pyrano[4,3‐ b ]pyran] scaffolds has been developed from 1,4‐diazabicyclo[2.2.2]octane (DABCO) catalyzed multi‐component reaction of isatin, malononitrile, and 4‐hydroxy‐6‐methyl‐2 H ‐pyran‐2‐one under mechanochemical strategy in ethanol as liquid‐assisted grinding (LAG) agent at room temperature in good to excellent yield (84–92%). This eco‐friendly approach aligns with green chemistry principles, offering a sustainable alternative to conventional routes by minimizing waste and avoiding hazardous solvents. The synthesized compounds were characterized by IR, 1 H, 1 3 C NMR, and high‐resolution mass spectrometry (HRMS). Frontier molecular orbital (FMO) analysis and global chemical reactivity profiling were performed to gain insight into the electronic structure, chemical stability, and potential reactivity of compounds 4i, 4k, 4l, and 4m. A molecular docking study evaluated the binding potential of these compounds against pancreatic α‐amylase for antidiabetic activity (PDB:1HNY; resolution: 1.80 Å). Among the synthesized derivatives, compounds 4j, 4h, and 4l exhibited the highest α‐amylase inhibitory activities, with IC 50 values of 75.98 ± 0.02, 76.56 ± 0.03, and 77.13 ± 0.05 µg/mL, respectively, compared with 68.13 ± 0.03 µg/mL for the reference drug acarbose. Derivative 4j showed the most potent inhibition, associated with the favorable structural features and molecular interactions of its propargyl‐substituted scaffold.