Molecular design and biological activity of novel quercetin imines: a multi-analytical approach to anti-inflammatory...

Quercetin is a natural flavonoid with proved anti-inflammatory activity; however, its therapeutic application is limited by poor bioavailability and rapid metabolic degradation. Structural modification through Schiff base formation offers an effective strategy to enhance its pharmacological activity. In the present study, six novel quercetin-derived imines were prepared by the condensation of quercetin with different aromatic amines, namely 4-aminoantipyrine (QAAP), 2-amino-4-methylphenol (QAMH), 4-aminophenol (QAOP), 4-chloro-o-phenylenediamine (QCPD), diphenylamine (QDPA), and o-phenylenediamine (QOPD). The synthesized Schiff bases were characterized by elemental analysis, UV-Visible, FT-IR, and ¹H and¹³C NMR spectroscopy, confirming successful Schiff base formation. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level were carried out to optimize molecular geometries and evaluate electronic properties. Molecular docking studies against the inflammatory target protein (PDB ID: 5IKR) revealed strong binding affinities ranging from -8.1 to -10.6 kcal/mol, with QOPD exhibiting the highest binding affinity (-10.6 kcal/mol), indicating favourable ligand-protein interactions. The anti-inflammatory activity of the synthesized compounds was experimentally evaluated using the human red blood cell (HRBC) membrane stabilization assay. All compounds demonstrated concentration-dependent membrane stabilization, with QAOP exhibiting the highest inhibition (74.46%) at 12.5 mg/mL, while QAAP showed the lowest IC₅₀ value (1.0854 mg/mL), indicating superior anti-inflammatory potency. The combined computational and experimental findings demonstrate that Schiff base derivatization significantly enhances the anti-inflammatory potential of quercetin by improving molecular interactions with inflammatory targets. These quercetin-derived imines represent promising lead molecules for the development of safer and more effective anti-inflammatory therapeutics.