Schiff Base Compound of ( <i>E</i> )‐1‐(((4‐chloro‐2‐hydroxyphenyl)imino)methyl)naphthalen‐2‐ol as CDK2 Inhibitory Agent: Structural Characterization, Density Functional Theory Computational, and In Silico studies

Compound (E)-1-(((4-chloro-2-hydroxyphenyl)imino)methyl)naphthalen-2-ol (HNC) was prepared by the reaction between 2-hydroxynaphthyl-1-carboxaldehyde and 2-amino-5-chlorophenol in an equimolar ratio and obtained in moderate yield. HNC was characterized using physicochemical and various spectroscopic techniques. The slow evaporation of a hot methanolic solution of HNC resulted in the formation of the zwitterionic ketoenamine form of HNC, and denoted as HNC'. Structurally, HNC' comprises one naphthoxide ring bridged with one chlorophenol ring by the azomethine group, and the torsion angle between the naphthoxide and the chlorophenol ring is 11.78°, speculating a nonplanar geometry. The density functional theory (DFT) at M06-2X/def2-TZVP level of theory described the facile enolimine-ketoenamine tautomerism and the highest occupied molecular orbital-lowest unoccupied molecular orbital gap of 5.757 eV for HNC, consistent with a moderately reactive scaffold. The inhibitory potential of HNC against cyclin-dependent kinases 2 (CDK2) was evaluated using molecular docking, molecular dynamics simulations, and molecular mechanics generalized Born surface area (MM-GBSA) free energy calculations. Docking results showed that HNC achieved a binding score of -8.75 kcal/mol, slightly lower than the reference inhibitor Roscovitine (RVT), which scored -9.41 kcal/mol. MM-GBSA calculations yielded ΔG_total values of -40.95 kcal/mol for HNC and -41.14 kcal/mol for RVT, suggesting comparable binding affinities. Generally, our findings pose HNC as a credible CDK2 inhibitor and tractable starting point for optimization toward selective antiproliferative agents.