Synthesis, Crystal Structure, Characterization, In Vitro and In Silico Evaluation of Vanillin-Pyrazole Heterocyclic...

Herein, we report the synthesis of a series of vanillin-pyrazole hybrids through a 1,3-dipolar cycloaddition reaction. The structures of these compounds were elucidated by various analytical methods, including NMR spectroscopy and HRMS, where compound 4a was further confirmed by x-ray diffraction. Their electronic properties were investigated through density function theory calculations at the B3LYP/6-311G(d,p). Moreover, the in vitro antioxidant activity of all compounds was evaluated by total antioxidant capacity and ferric reducing antioxidant power assays. As a result, compound 4a had the smallest HOMO-LUMO gap, indicating high electron-donating ability, while 4b showed the highest EHOMO (-5.688 eV), lowest hardness, and a narrow gap (∼4.20 eV). Additionally, compounds 4a-c, 6a, and 6b exhibited an important antioxidant activity with IC₅₀ values ranging from 19.59 to 30.37 µM in the TAC method, compounds 4a and 6b showed remarkable activity of IC₅₀ (92.13 and 102.64 µM, respectively) in the FRAP assay. Molecular docking and molecular dynamics simulations were performed to investigate the binding mode and behavior of 4a-c and 6b with human cytochrome P450 (CYP2C9) and human carbonyl reductase-1 (HCBR1), which were in good agreement with the observed antioxidant effects. These assessments revealed that vanillin-pyrazole hybrids could be used as promising derivatives in the quest for potent antioxidants. The ADMET properties indicated favorable drug-like properties for all compounds. Overall, compounds 4a, 4b, and 6b combine potent antioxidant activity with promising pharmacokinetic characteristics, highlighting vanillin-pyrazole hybrids as potential drug candidates for antioxidant therapy.