The research employed zirconyl oxychloride as a catalyst in a reaction involving pyrazole aldehyde, (thio)urea, and acetyl acetone to establish an aqueous approach for synthesizing 3,4-dihydropyrimidinone derivatives (compounds 4a-j) with potential claims as antidiabetic agents. FT-IR, HR-MS,H NMR andC NMR were employed to analyze the synthesized compounds. The HOMO-LUMO analysis was performed to evaluate the stability of the synthesized derivatives. The antioxidant activity of synthesized derivatives was evaluated by DPPH and nitric oxide radical scavenging tests, while the in vitro antidiabetic efficacy was determined by α-amylase and α-glucosidase enzyme inhibition assays. Molecular docking, molecular dynamics simulations, and molecular mechanics were undertaken to assess the binding efficacy of the synthesized derivatives to target proteins associated with antidiabetic (pancreatic α-amylase and α-glucosidase) and antioxidant (human PDI-peroxidase) activities. According to α-amylase and α-glucosidase study, the derivatives 4g, 4i, and 4e shown significant antidiabetic activity. Likewise, compounds 4j and 4a effectively inhibited the free radicals, DPPH and nitric oxide. Excellent binding interactions were recorded with the docking scores of -7.198 kcal/mol for α-amylase (1OSE), -6.242 kcal/mol for α-glucosidase (5ZCB), and - 6.502 kcal/mol for PDI-peroxidase (3KIJ) for the 4j, 4j, and 4e derivatives. In-silico toxicity prediction studies indicate that synthesized chemicals will be less harmful. Hepatotoxicity and clinical toxicity studies indicate general safety and a minimal risk of liver injury. So, while these derivative molecules may be useful in diabetes treatment, further in vivo study is required to demonstrate their usefulness and safety. 1 13
