In silico and in vitro insights into tyrosinase inhibitors with a 2-thioxooxazoline-4-one template

The beta-phenyl-alpha,beta-unsaturated carbonyl (PUSC) scaffold confers tyrosinase inhibitory activity, and in the present study, 16 (Z)-5-(substituted benzylidene)-3-phenyl-2-thioxooxazolidin-4-one analogues containing this scaffold were synthesized. Mushroom tyrosinase inhibitory activities were examined. Compound 1c (IC50 = 4.70 +/- 0.40 mu M) and compound 1j (IC50 = 11.18 +/- 0.54 mu M) inhibited tyrosinase by 4.9 and 2.1-fold, respectively, and did so more potently than kojic acid (IC50 = 23.18 +/- 0.11 mu M). Kinetic analysis of tyrosinase inhibition revealed that 1c and 1j inhibited tyrosinase competitively. Results of docking simulation with mushroom tyrosinase using four docking programs suggested that 1c and 1j bind more strongly than kojic acid to the active site of tyrosinase and supported kinetic findings that both compounds are competitive inhibitors. The docking results of human tyrosinase homology model indicated that 1c and 1j can also strongly inhibit human tyrosinase. EZ-cytox assays revealed 1c and 1j were not cytotoxic to B16F10 melanoma cells. The effects of 1c and 1j on cellular tyrosinase activity and melanin production were also investigated in alpha-MSH- and IBMX-co-stimulated these cells. Both compounds significantly and dose-dependently reduced tyrosinase activity, and at 10 mu M were more potent than kojic acid at 20 mu M. Compounds 1c and 1j also inhibited melanogenesis, which suggested that the inhibitory effects of these compounds on melanin production were mainly attributable to their inhibitions of tyrosinase. These results indicate that compounds 1c and 1j with the PUSC scaffold have potential use as whitening agents for the treatment of hyperpigmentation-associated diseases. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.

Automated summary

The study synthesized 16 analogues containing the PUSC scaffold, with compounds 1c and 1j showing strong competitive inhibition of tyrosinase. This indicates the potential whitening properties of these compounds.