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 H-1 and C-13 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. (C) 2011 Elsevier B.V. All rights reserved.