Tyrosinase Inhibition by Novel Benzimidazole-thione Schiff Base Derivatives

Abstract

Background: Tyrosinase is the enzyme responsible for the conversion of tyrosine to dopaquinone, which is related to melanoma, neurodegenerative disorders, freckles, pigmented acne and age spots. Controlling the tyrosinase activity could be an important way for treating overproduction of melanin. Objective: The development of safe and specific tyrosinase inhibitors could be used to treat hypermelanosis. Methods: 5-nitro-1H-benzo[d]imidazole-2(3H)-thione was synthesized from 4-nitro-o-phenylenediamine and carbon disulfide. The nitro group of 5-nitro-1H- S-1 ESI-HRMS benzo[d]imidazole-2(3H)-thione was reduced with iron powder. The 5-amino-1H-benzo[d]imidazole- 2(3H)-thione Schiff base derivatives were obtained by the reaction of 5-amino-1H-benzo[d]imidazole-2(3H)-thione with substituted benzaldehyde. The tyrosinase inhibitory activities were investigated. The studies of kinetic analysis, metalchelating properties, docking and cytotoxicity were also performed. Results: All of the compounds showed strong tyrosinase inhibitory activities with 5-((4-nitrobenzylidene) amino)-1H-benzo [d]imidazole-2(3H)-thione (S-4) as the best tyrosinase inhibitor with an IC50 value of 4.8 ± 1.4 nM. Compound S-4 exhibited mixed type inhibition of mushroom tyrosinase, with Ki 15 nM and Kis 42 nM. Copper binding to S-4 was detected spectrophotometrically and 1-100 μΜ S-4 displayed negligible cytotoxicity to murine B16 melanoma cells. Conclusion: Our results demonstrated that these benzimidazolethione Schiff base derivatives might be promising candidates as tyrosinase inhibitors.