Targeting Lung Cancer With Carvacrol-Triazole-Arylidene Hydrazide Hybrids: In Vitro and In Silico Cytotoxicity Assessments.

In this study, a series of 16 arylidene hydrazide derivatives (7a-7p), hybridized with the natural product carvacrol, were successfully synthesized starting from anthranilic acid methyl ester. The cytotoxic effects of these compounds were examined against two different cell lines, A549 and BEAS-2B. Additionally, in silico studies were conducted to investigate the ligand-protein binding modes and their stabilities. Lastly, the predicted absorption, distribution, metabolism, and excretion (ADME) properties were also explored. The compounds' structures were confirmed through meticulous NMR and MS spectral analyses. Biological assays indicated notable cytotoxic effects against human lung cancer (A549) and non-tumorigenic lung epithelial (BEAS-2B) cell lines, with compounds 7j, 7k, and 7l demonstrating high selectivity indices (SIs) and low IC values against A549 cells, signifying potent selective anticancer activity. Molecular docking and molecular dynamics (MD) simulations identified key binding interactions of these compounds with epidermal growth factor receptor (EGFR) and BRAF proteins, emphasizing the importance of residues such as Lys-745 and Phe-856 in EGFR and Lys-483 in BRAF. Stability of these complexes was confirmed through 100 ns MD simulations. ADME analysis revealed favorable pharmacokinetic properties for the prominent compounds, particularly 7k. These results suggest that arylidene hydrazide derivatives, especially 7k, are promising selective anticancer agents with potential for further development.