Design, Synthesis, and Biological Evaluation of Novel Hybrids Containing Dihydrochalcone as Tyrosinase Inhibitors to Treat Skin Hyperpigmentation

Excessive melanin deposition may lead to a series of skin disorders. The production of melanin is carried out by melanocytes, in which the enzyme tyrosinase performs a key role. In this work, we identified a series of novel tyrosinase inhibitor hybrids with a dihydrochalcone skeleton and resorcinol structure, which can inhibit tyrosinase activity and reduce the melanin content in the skin. Compound 11c possessed the most potent activity against tyrosinase, showing IC50 values at nanomolar concentration ranges, along with significant antioxidant activity and low cytotoxicity. Furthermore, in vitro permeation tests, supported by HPLC analysis and 3D OrbiSIMS imaging visualization, revealed the excellent permeation of 11c. More importantly, compound 11c reduced the melanin content on UV-induced skin pigmentation in a guinea pig model in vivo. These results suggest that compound 11c may serve as a promising potent tyrosinase inhibitor for the development of a potential therapy to treat skin hyperpigmentation.

Automated summary

Excessive melanin deposition can cause various skin disorders. We discovered a series of novel tyrosinase inhibitor hybrids that can inhibit tyrosinase activity and reduce melanin content in the skin. Compound 11c showed the most potent activity against tyrosinase, with nanomolar IC50 values, significant antioxidant activity, and low cytotoxicity. It also exhibited excellent permeability in vitro and reduced melanin content in a guinea pig model of UV-induced skin pigmentation. Compound 11c holds promise as a potential therapy for treating skin hyperpigmentation.