Discovery of -thiourea derivatives as potent tyrosinase inhibitors: combined experimental and computational study.

Tyrosinase, a key enzyme in melanin synthesis, serves as a primary target for developing depigmenting agents. The search for novel tyrosinase inhibitors is needed due to the adverse effects of current inhibitors. This study evaluated 16 -thiourea derivatives using and methods, identifying compound , with chlorine substituents, as the most potent inhibitor. Compound outperformed kojic acid in inhibiting mushroom tyrosinase activity and interacted with catalytic copper ions and active site residues, as revealed by molecular docking and copper-chelating assay. Molecular dynamics simulation and MM/PBSA-based free energy calculations confirmed the greater stability and binding affinity of the compound -tyrosinase complex in an aqueous environment compared to kojic acid-tyrosinase complex. Melanin assay revealed that compound significantly suppressed melanin production in B16F10 melanoma cells, showing stronger anti-melanogenic activity than kojic acid. Drug-likeness predictions confirmed its compliance with Lipinski's rule of five, supporting -thiourea derivatives as promising tyrosinase inhibitors.