Integrating synthesis, density functional theory studies, molecular docking, cytotoxicity, and ADMET predictions, this study identifies [Cu^II(salen)(H₂O)₂] (2) as a selective anticancer agent. Docking and in vitro assays highlight its favorable target interactions, selective anticancer activity, and reduced toxicity toward normal fibroblasts, supporting its potential as a scaffold for safer metal-based cancer therapies.

Transition metal complexes are considered a significant treatment for cancer diseases because of their efficacy toward cancer cells. However, most of these compounds have limited potential toward cancer cells due to their organic backbone structure. Here, the synthesis and anticancer screening of three different ligand structures of salen copper(II) complexes are reported: [Cu^II(salophen)(H₂O)₂] (1), [Cu^II(salen)(H₂O)₂] (2), and [Cu^II(etho-salen)(H₂O)₂] (3). Using density functional theory-optimized structures, docking active site interactions are evaluated to predict the activity of salen-type ligands and their copper(II) complexes against cyclin-dependent kinase 5 (Cdk5 ) and aromatase cytochrome (P450) proteins. The molecular docking study reveals that among all studied ligands and complexes, [Cu^II(salen)(H₂O)₂] (2) has the best docking score value, S = −8.79 and −7.73, with the lowest root mean square deviation (RMSD = 1.02 and 1.09) against proteins Cdk5 and P450, respectively. Anticancer activity against MCF-7 and HCT-116 cell lines reveals that [Cu^II(salen)(H₂O)₂] (2) shows favorable behavior with IC₅₀ values of 212.5 and 98.9 μm, respectively. Its parent ligand 2 shows lower potency, with IC₅₀ values of 404.7 μm in MCF-7 and 305.2 μm in HCT-116. Notably, copper(II) complexes display reduced toxicity rather than cisplatin toward normal HFF-1 fibroblasts, indicating a more favorable therapeutic window.