Imidazole-2-thione derivatives as new selective anticancer agents with anti-metastatic properties: synthesis and pharmacological evaluation
- J Enzyme Inhib Med Chem. 2026 Dec;41(1):2607820. doi: 10.1080/14756366.2025.2607820.
- 1. Department of Organic Chemistry, Kaunas University of Technology, Kaunas, Lithuania.
- 2. Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Gdansk, Poland.
- 3. Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology, Lviv Polytechnic National University, Lviv, Ukraine.
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.