Analogs of 5-(substituted benzylidene)hydantoin as inhibitors of tyrosinase and melanin formation.

BACKGROUND Many tyrosinase inhibitors find application in cosmetics and pharmaceutical products for the prevention of the overproduction of melanin in the epidermis. A series of 5-(substituted benzylidene)hydantoin derivatives 2a-2k were prepared, and their inhibitory activities toward tyrosinase and melanin formation were evaluated. METHODS The structures of the compounds were established using (1)H and (13)C NMR spectroscopy and mass spectral analyses. All the synthesized compounds were evaluated for their mushroom tyrosinase inhibition activity. RESULTS The best results were obtained for compound 2e which possessed hydroxyl group at R(2) and methoxy group at R(3), respectively. We predicted the tertiary structure of tyrosinase, simulated its docking with compound 2e and confirmed that this compound interacts strongly with mushroom tyrosinase residues as a competitive tyrosinase inhibitor. In addition, we found that 2e inhibited melanin production and tyrosinase activity in B16 cells. CONCLUSIONS Compound 2e could be considered as a promising candidate for preclinical drug development in skin hyperpigmentation applications. GENERAL SIGNIFICANCE This study will enhance understanding of the mechanism of tyrosinase inhibition and will contribute to the development of effective drugs for use hyperpigmentation.