Discovery of New Thiourea Derivatives as Potential SIRT Inhibitors

Objective: This study aimed to design and synthesize novel thiourea-based compounds targeting Sirtuins (SIRTs), a class of histone deacetylase enzymes implicated in various cellular processes, including cancer, and to evaluate their cytotoxic potential against colon cancer cells. Methods: Virtual modeling and molecular docking studies were conducted to design the compounds and assess their interaction with SIRT enzymes. Compounds showing acceptable docking scores were selected for organic synthesis. The final compounds (MA-1 to MA-6) were synthesized and characterized using FTIR, ¹H-NMR, and ¹³C-NMR spectroscopy. Cytotoxicity studies were performed on SW480 colon cancer cells to evaluate the biological activity of the synthesized compounds. Results: All synthesized compounds exhibited promising cytotoxicity against SW480 colon cancer cells, with MA-2 demonstrating a particularly strong effect. The half-maximal inhibition concentration (IC50) of the compounds was in the single-digit micromolar range, comparable to established SIRT inhibitors Selisistat and AGK2. Conclusion: The thiourea-based compounds synthesized in this study, especially MA-2, showed significant potential as SIRT inhibitors with cytotoxic activity against colon cancer cells. These results warrant further investigation into their therapeutic potential.