Design, Synthesis, and Multidimensional In Silico Profiling of Novel Heterocyclic Azo-Imine Hybrids as Potent VEGFR2 Inhibitors

Target-directed disruption of the VEGFR2 kinase cascade remains a cornerstone strategy in anti-angiogenic oncology therapeutics; however, severe systemic toxicities, acquired resistance profiles of current drugs, and tedious multi-step chromatographic isolation bottlenecks in hybrid molecule synthesis present major ongoing challenges. To address these limitations, this study presents the rational design and efficient fabrication of a novel series of heterocyclic azo-imine hybrids (3a–j) through a high-yield (92–78%), chromatography-free one-pot acid-catalyzed condensation protocol. These scaffolds strategically integrate an Imatinib-inspired aniline core to evaluate their multi-kinase inhibitory potential against the VEGFR2 cascade. Quantum chemical simulations, executed within the DFT framework at the B3LYP/6-311++G(d,p) level of theory in DMSO continuum, mapped the fundamental electronic topology, global reactivity profiles, and intramolecular charge transfer (ICT) gradients of the library. Molecular docking simulations against the inactive ‘DFG-out’ state of VEGFR2 (PDB ID: 4ASD) demonstrated exceptional geometric complementarity, outperforming the reference drug Sorafenib in binding affinity (up to −13.1 kcal/mol). Thermodynamic binding free energy calculations identified ligand 3h as the most exergonic binder (ΔGbind = −98.662 kJ/mol vs. Sorafenib: −54.029 kJ/mol), while an explicit 250-ns molecular dynamics simulation trajectory confirmed high structural resilience and steady induced-fit adaptations under dynamic biological conditions. Collectively, these findings support the potential of these novel scaffolds as VEGFR2-targeting compounds and warrant further experimental investigation to establish their biological activity.