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.