Design, synthesis, and anti-melanogenic efficacy of 2-mercaptobenzoxazoles with nanomolar tyrosinase activity inhibition.

[Display omitted] • 2-MBO analogs showed stronger tyrosinase inhibition potency than phenylthiourea. • In B16F10 cells, 2-MBO analogs strongly inhibited melanin production. • Their anti-melanogenic effect was due to inhibition of cellular tyrosinase activity. • Their tyrosinase inhibitory activity was due to chelation of tyrosinase copper ions. • 2-MBO analogs are promising candidates for treating skin-pigmentation disorders. Tyrosinase is a metalloenzyme that contains copper(II) ions. We designed and synthesized eight known low-molecular-weight 2-mercaptobenzoxazole (2-MBO) analogs as tyrosinase inhibitors. Our focus was on the mercapto functional group, which interacts with copper ions. Analogs 1 – 3 exhibited mushroom tyrosinase inhibitory activity at the nanomolar level and demonstrated strong potency with extremely low half-maximal inhibitory concentration (IC 50) values of 80–90 nM for l -dopa and 100–240 nM for l -tyrosine. Analogs 2 , 4 , and 5 showed the most potent anti-melanogenic effects in B16F10 cells, and their mode of action was demonstrated by kinetic analysis. Their anti-melanogenic effects were similar to the tyrosinase inhibition results, suggesting that their anti-melanogenic effects could be attributed to their tyrosinase inhibitory ability. Experiments using copper-chelating activity assays and changes in tyrosinase inhibitory activity with and without CuSO 4 demonstrated that 2-MBO analogs inhibit tyrosinase activity by chelating the copper ions of tyrosinase. In conclusion, the 2-MBO analogs show potential as anti-melanogenic agents with potent tyrosinase inhibitory activity. [ABSTRACT FROM AUTHOR]