Structure–activity optimization of Deferasirox–derived aroyl hydrazones: Synthesis, DFT characterization, and mechanistic insights into selective anticancer activity against colon and breast cancer

Dysregulated iron metabolism is increasingly recognized as a hallmark of tumor progression in solid malignancies, including colon and breast cancers. Deferasirox (DFX), an oral Fe(III) chelator, exhibits anticancer activity; however, its structural optimization may enhance potency and selectivity. Here, six novel DFX-based aroyl hydrazone derivatives were synthesized, structurally characterized, and evaluated in vitro. Quantum chemical calculations and two-dimensional NMR confirmed their configurations, while molecular dynamics simulations demonstrated stable protein–ligand interactions. Compound 5e exhibited potent and selective cytotoxicity against triple-negative breast cancer (MDA-MB-231) and metastatic colon cancer (SW620) cells. Mechanistic studies revealed that 5e induces apoptosis and cell cycle arrest in a dose-dependent manner, with reactive oxygen species (ROS) generation playing a central role. Increased oxidative stress triggered autophagy, as evidenced by upregulation of Beclin-1, ATG5, and LC3 conversion. Co-treatment with the ROS scavenger N-acetylcysteine significantly reversed these effects, confirming the ROS-mediated mechanism. These findings highlight compound 5e as a multi-targeted anticancer agent warranting further in vivo and combination therapy investigations.