Exploring the Anticancer Activity, Molecular Docking and Density Functional Theory Analysis of α‐Naphthalene Acetic Acid Derivatives

ABSTRACT This study focuses on the anticancer activity of four synthetic hydrazone Schiff base derivatives of α‐naphthalene acetic acid. These compounds were structurally deduced using modern spectroscopic techniques ( 1 H‐, 13 C–NMR and mass). Compound 3 (IC 50 = 13.25 ± 0.005 µM), 4 (IC 50 = 17.78 ± 0.001 µM) and 5 (IC 50 = 21.49 ± 0.098 µM) presented excellent activity, while compound 6 (IC 50 = 94.38 ± 0.014 µM) showed lesser activity against malignant glioma (U‐87 cell line). The compounds were also screened against human embryonic kidney (HEK293) cell line to examine the selective cytotoxic actions of the compounds towards the normal cells. The results obtained from their percentage viabilities showed that the compounds are less vulnerable against HEK293 cells and increases the death of cancer cells. The electronic indices (ΔƐ, ω) partially explain DOX's potency; the reduced efficacy of compounds (3‐6) with longer alkoxy chains underscores the dominance of pharmacokinetic factors. The docking interactions with residues like Met742, Cys773, and Asp831, indicate that longer chains compounds (5 and 6) penetrate hydrophobic sub‐pockets, boosting interaction energy (EInt) values. The naphthalene ring may engage in π‐π stacking with aromatic residues, enhancing binding interaction. Compound 5 's profile mirrors that of known epidermal growth factor (EGFR) inhibitors like erlotinib, suggesting high inhibitory potential.