Design and synthesis of 4-(2,4-dihydroxyphenyl)thiazole-2-carboxamide derivatives as novel tyrosinase inhibitors: in vitro and in vivo validation.

Abstract

Melanin is essential for protecting human skin against harmful ultraviolet (UV) irradiation and environmental pollutants. However, excessive melanin accumulation in the epidermis can affect aesthetics, cause psychological distress, and reduce quality of life. Despite the development and utilization of several well-known tyrosinase (TYR) inhibitors as skin-whitening agents in cosmetics to address hyperpigmentation concerns, there remains a growing demand in the cosmetics market for safer, more efficient, and diverse skin-whitening agents. Guided by the binding model of thiamidol with TYR, this study synthesized and characterized 26 4-(2,4-dihydroxyphenyl)thiazole-2-carboxamide derivatives, evaluating their anti-TYR activities. Among these compounds, compound 4 exhibited the strongest anti-TYR activity (IC₅₀ = 1.51 μM) and effectively inhibited melanogenesis in the in vitro B16 cell model. Although its anti-TYR activity and anti-melanogenic effect in vitro were less than those of thiamidol (IC₅₀ = 0.72 μM), its depigmenting effect on the in vivo zebrafish embryo model was comparable to thiamidol. Additionally, compound 4 demonstrated excellent biocompatibility and exhibited lower toxicity compared to thiamidol. Overall, these results suggest that compound 4 holds potential as a promising candidate for application as a skin-whitening cosmetic ingredient.