Imidazole-2-thione derivatives as new selective anticancer agents with anti-metastatic properties: synthesis and...

Imidazole scaffolds are attractive in drug design for bioactivity and synthetic accessibility. We developed S-substituted imidazole-2-thione derivatives, focusing on compound 24, which showed potent cytotoxicity against lung, cervical, and colorectal cancer cells with submicromolar IC₅₀ and selectivity over fibroblasts. Mechanistic analyses revealed G1 arrest, caspase-dependent apoptosis, and p-γH2AX accumulation. Importantly, compound 24 strongly inhibited A-549 cell migration and invasion in both 2D and 3D assays, correlating with downregulation of MMP-2, MMP-9, and hTERT. In vitro enzyme assays further confirmed that compound 24 directly inhibits MMP-9 activity. In vivo, 24 suppressed tumour growth and vasculotropic spread in the CAM model without detectable toxicity. Docking and dynamics simulations confirmed stable binding to MMP-2 and MMP-9 active sites. These results identify compound 24 as a promising anticancer agent with both cytotoxic and anti-metastatic properties, supporting its further preclinical investigation.