Identification of (Z)-2-benzylidene-dihydroimidazothiazolone derivatives as tyrosinase inhibitors: Anti-melanogenic effects and studies.

As part of our continuous search for novel tyrosinase inhibitors, we designed 5,6-dihydroimindazo[2,1-]thiazol-3(2)-one (DHIT) derivatives based on the structure of MHY773; a potent tyrosinase inhibitor with a 2-iminothiazolidin-4-one template. Of the 11 DHIT derivatives synthesized using a Knoevenagel condensation, three DHIT derivatives (IC = 36.14 ± 3.90 μM), (IC = 0.88 ± 0.91 μM), and (IC = 17.10 ± 1.01 μM) inhibited mushroom tyrosinase more than kojic acid (IC = 84.41 ± 2.87 μM). Notably, compound inhibited mushroom tyrosinase around 100- and 3.3-fold more potently than kojic acid and MHY773, respectively. Lineweaver-Burk plots demonstrated that compounds and competitively inhibited mushroom tyrosinase, and docking results supported our kinetic results and indicated that these two compounds bind more strongly to the active site of tyrosinase than kojic acid. Docking simulation results using a human tyrosinase homology model confirmed the abilities of and to strongly inhibit human tyrosinase. B16F10 murine melanoma cells were used to investigate whether these two compounds display tyrosinase inhibitory activities and anti-melanogenesis effects in cells. Both compounds were found to significantly and dose-dependently inhibit cellular tyrosinase activity and intracellular and extracellular melanin production more potently than kojic acid. The similarities observed between the cellular tyrosinase and melanogenesis inhibitory effects of and suggest their observed anti-melanogenic effects were due to tyrosinase inhibition. These results indicate that compounds and , which possess the DHIT template, are promising candidates as anti-browning agents and therapeutic agents for hyperpigmentation disorders.