DES-Promoted Synthesis of 3,4-Dihydropyrimidinones and Their Antidiabetic and Antioxidant Evaluation Supported With Computational Studies

A series of 3,4-dihydropyrimidinone (DHPM) derivatives was synthesized using a green deep eutectic solvent (DES) system composed of ZnCl₂ and urea, which acted simultaneously as solvent, catalyst, and in situ substrate (urea). The synthesized compounds were evaluated for their antidiabetic potential via α-glucosidase and α-amylase inhibition assays, as well as for antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and nitric oxide (NO) scavenging assays. Among the series, compound 3f exhibited superior inhibitory activity against α-glucosidase (IC₅₀ = 35.25 µM) and α-amylase (IC₅₀ = 38.61 µM), being ∼2.3- and ∼2.6-fold more potent, respectively, than the standard drug acarbose. In antioxidant evaluations, compound 3i (IC₅₀ = 35.60 µM) demonstrated ∼2.9-fold higher activity than gallic acid in the DPPH assay, whereas 3d (IC₅₀ = 30.70 µM) and 3a (IC₅₀ = 44.52 µM) showed ∼3.8- and ∼1.5-fold higher activity in FRAP and NO scavenging assays, respectively. Molecular docking studies revealed key hydrogen bonding interactions of 3f with the active site residues of both enzymes, supported by favorable docking scores. Furthermore, density functional theory (DFT) studies revealed favorable electronic and reactivity profiles, whereas ADME/T predictions indicated good drug-likeness. Overall, compound 3f shows strong potential as a lead antidiabetic agent for managing postprandial hyperglycemia.