Synthesis, characterization, and integrated in silico studies of 4-Aminoantipyrine-derived Schiff bases as promising antimicrobial, antioxidant, and cytotoxic agents: DFT, ADME, and molecular docking studies
Abstract
This study reports the synthesis, structural characterization, experimental and computational evaluation of a series of Schiff base derivatives (3a–3f) obtained from 4-aminoantipyrine via condensation with various aromatic and heteroaromatic aldehydes. The synthesized compounds were fully characterized by FT-IR, 1H NMR, and mass spectrometry, which showed the formation of preferential imine linkages. The antibacterial activity was evaluated against Staphylococcus aureus and Acinetobacter baumannii using the agar well-diffusion method. All compounds showed significant antibacterial activity, with compound 3a showing the highest activity against both bacterial strains (IZD = 23 mm and 20 mm, respectively). Antioxidant screening using the DPPH assay showed a wide range of radical scavenging activity, with IC50 values ranging from 56.3 to 423.1 μg/mL, revealing the influence of substituent electronic effects on antioxidant activity. Cytotoxicity evaluation against HepG2 cells showed that compounds 3a, 3e, and 3 f exhibited concentration-dependent cytotoxicity, with compound 3 f showing the highest inhibition (63.03% at 500 μg/mL), while exhibiting low cytotoxicity toward normal Vero cells. DFT calculations performed at the B3LYP/6-311G (d, p) level provided insight into the electronic properties and chemical reactivity of the synthesized compounds, while the Absorption, Distribution, Metabolism, and Excretion (ADME) predictions suggested favorable pharmacokinetic profiles. Molecular docking studies showed strong binding affinities for DNA gyrase (PDB ID: 4DUH) and VEGFR2 kinase (PDB ID: 3VHE), with compound 3e showing the highest binding affinity for DNA gyrase (−8.2 kcal/mol) and compound 3a, 3e, and 3 f exhibited the highest binding affinities toward VEGFR2 (−10.3 kcal/mol). The determined biological activities were consistent with the docking results, supporting these derivatives as promising multifunctional scaffolds for the development of novel antibacterial and anticancer agents.