A Novel Synthesized Tyrosinase Inhibitor: (E)-2-((2,4-Dihydroxyphenyl)diazenyl)phenyl 4-Methylbenzenesulfonate as an Azo-Resveratrol Analog

We synthesized a novel series of (E)-2-((substituted phenyl)diazenyl)phenyl 4-methylbenzenesulfonate derivatives (2 and 3) and (E)-2-((substituted phenyl)diazenyl)phenol derivatives (4 and 5), and conducted an evaluation in order to determine their inhibitory effects on mushroom tyrosinase, with the aim of discovering a tyrosinase inhibitor. Most of the compounds (3-5) exhibited higher inhibitory effects than kojic acid (IC50 = 49.08 mu m), a representative tyrosinase inhibitor. A novel synthesized compound, (E)-2-((2,4-dihydroxyphenyl)diazenyl)phenyl 4-methylbenzenesulfonate (3), showed the best results with an IC50 of 17.85 mu m, and showed competitive inhibition on Lineweaver-Burk plots, as further confirmed by the docking results. In addition, active compounds 3-5 were not cytotoxic to cultured B16F10 cells at the concentrations tested, and inhibited both tyrosinase and melanin synthesis. Therefore the active compounds (3-5) might be considered excellent candidates for use in the development of therapeutic agents for diseases associated with hyper-pigmentation.