Novel Hydrazone Derivative with 4-(4-Aminophenoxy)-N-methylpicolinamide Moiety: Spectroscopic, Molecular Dynamics, and Docking Studies for Potential Anticancer Activity

Abstract

Protein kinases such as RAF1 and VEGFR2 regulate key pathways in cell prolifera-tion, differentiation, and angiogenesis, making them promising cancer targets. However, kinase inhibitor efficacy is often limited by off-target effects, poor pharmacokinetics, and resistance. Hydrazone derivatives, with structural flexibility and multi-target potential, offer a valuable scaffold. Here, we designed and syn-thesized a novel hydrazone incorporating the 4-(4-aminophenoxy)-N-methylpicolinamide pharmacophore to achieve selective kinase inhibition. The compound was characterized via 1H/13C-NMR, FT-IR, and mass spectrometry, confirming its structure and purity. DFT (B3LYP/6-311++G(d,p)) calculations sup-ported the experimental data, providing optimized geometry and electronic in-sights. Molecular docking against RAF1 (PDB: 4ASD) and VEGFR2 (PDB: 5HI2) indicated strong binding through hydrogen bonds, π–π stacking, and hydrophobic interactions. Molecular dynamics simulations (100 ns, YASARA) confirmed lig-and–protein complex stability, minimal RMSD fluctuations, and consistent hydro-gen bond occupancy under physiological conditions.