Discovery of Novel Dihydroxyphenol Tyrosinase Inhibitors for Treatment of Pigmentation: From Enzyme Screening to Three-Dimensional Human Skin Melanin Evaluation

Tyrosinase
inhibitors constitute a class of pharmacological
agents
with broad applications in both therapeutic and cosmetic formulations,
owing to the modulation of skin pigmentation. However, the clinical
development of these agents has been hampered by suboptimal efficacy
profiles and safety considerations. In the present study, we employed
a rational pharmacophore hybridization approach to design novel tyrosinase
inhibitors. Systematic evaluation of the synthesized compounds revealed
potent tyrosinase inhibition, with the majority exhibiting nanomolar-range
IC50 values, representing a significant improvement over
kojic acid and arbutin. The optimal compound III19 demonstrated
exceptional performance across multiple validation models, including
melanin production assays and zebrafish antipigmentation evaluation,
and maintained robust efficacy in a reconstructed 3D melanocytic human
skin test. Furthermore, preliminary cytotoxicity, skin permeability,
and metabolic stability evaluation of compound III19 was
also conducted. These results advanced the understanding of structure–activity
relationships in phenolic tyrosinase inhibitors and provided promising
leads for discovering novel antipigmentation agents.