Tailored pyrazolone–oxadiazole frameworks: synthetic execution, functional enzyme studies, and comprehensive docking–DFT-based antidiabetic investigation

AIM: This study aimed to design, synthesize, and biologically evaluate a novel series of pyrazolone-derived oxadiazole Schiff base derivatives as potential anti-diabetic agents. MATERIALS AND METHODS: A library of Schiff base derivatives was synthesized and structurally characterized using ¹H NMR, ¹³C NMR, and HREI-MS techniques. The anti-diabetic potential was evaluated through in vitro α-amylase and α-glucosidase inhibition assays. The most active compounds were further analyzed by molecular docking and molecular dynamics (MD) simulations to explore binding interactions and stability within enzyme active sites. Density functional theory (DFT) calculations were performed to assess electronic properties, including HOMO-LUMO energy gaps, while ADMET predictions were conducted to evaluate pharmacokinetic and drug-likeness profiles. RESULTS: The compounds exhibited moderate to excellent inhibitory activity against both enzymes. Among them, analogs 1-3 showed the highest potency, with analog 3 identified as the lead compound, displaying IC₅₀ values of 3.10 ± 0.20 µM (α-amylase) and 3.60 ± 0.20 µM (α-glucosidase). Computational studies supported strong binding affinity and stable interactions, while DFT and ADMET analyses indicated favorable electronic and pharmacokinetic properties. . CONCLUSION: These findings highlight pyrazolone-oxadiazole Schiff base derivatives, particularly analog 3, as promising anti-diabetic candidates for further optimization and preclinical studies.