Design and Synthesis of Triazole‐Based Imidazolium Salts as Potent Integrin‐Linked Kinase (ILK) Inhibitors for Anti‐Metastatic Breast Cancer Therapy

Abstract Breast cancer metastasis remains a critical challenge, necessitating targeted therapies that disrupt key signaling pathways in tumor progression. Integrin‐linked kinase (ILK), a key regulator of cell adhesion, migration, and survival via the AKT/NF‐κB axis, is a promising target for anti‐metastatic drug development. This study reports the synthesis and evaluation of C2‐substituted and unsubstituted imidazolium–triazole derivatives as potential ILK modulators. Compounds were synthesized using Cu(I)‐catalyzed azide–alkyne cycloaddition and characterized by FTIR, NMR, and mass spectrometry. To explore upstream molecular interactions, docking studies were conducted using the CXCR4 receptor (PDB ID: 3ODU), functionally linked to ILK activation in metastasis. Compound 14 demonstrated high binding affinity (–9.3 kcal/mol), interacting with Trp94, Asp97, and Ile204, and maintained stability during 100 ns molecular dynamics simulations. In vitro cytotoxicity against MCF‐7 cells identified Compound 6 as the most potent (IC 50 = 170.58 ± 0.3 µg/mL), with Compound 14 also showing notable activity (IC 50 = 200.84 ± 0.7 µg/mL). Structure–activity relationship analysis (SAR) revealed that aromatic and hydrophobic groups enhanced efficacy. These results suggest that imidazolium–triazole hybrids are promising modulators of the CXCR4–ILK–AKT/NF‐κB axis and hold potential for further development as anti‐metastatic agents in breast cancer therapy.