Inhibitory Effect of Curcumin-Inspired Derivatives on Tyrosinase Activity and Melanogenesis.

Tyrosinase is a well-known copper-containing metalloenzyme typically involved in the synthesis of melanin. Recently, curcumin and several synthetic derivatives have been recognized as tyrosinase inhibitors with interesting anti-melanogenic therapeutic activity. In this study, three curcumin-inspired compounds , and were prepared in yields ranging from 60 to 88 % and spectrophotometric, electrochemical, in vitro and in silico analyses were carried out. The viability of PC12 cells, a rat pheochromocytoma derived-cell line, with compounds , and , showed values around 80% at 5 µM concentration. In cell proliferation assays, compounds , and did not show significant toxicity on fibroblasts nor melanoma cells up to 10 µM with viability values over 90%. The inhibition of tyrosinase activity was evaluated both by a UV-Vis spectroscopic method at two different concentrations, 0.2 and 2.0 µM, and by amperometric assay with IC for compounds , and ranging from 11 to 24 nM. Melanin content assays on human melanoma cells were performed to test the capability of compounds to inhibit melanin biosynthesis. All compounds exerted a decrease in melanin content, with compound being the most effective by showing a melanogenesis inhibition up to four times greater than arbutin at 100 µM. Moreover, the antioxidant activity of the selected inhibitors was evaluated against HO in amperometric experiments, whereby compound was about three times more effective compared to compounds and . The tyrosinase X-ray structure of crystal was used to carry out molecular docking studies in the presence of compounds , and in comparison with that of kojic acid and arbutin, two conventional tyrosinase inhibitors. Molecular docking of compounds and confirmed the high affinity of these compounds to tyrosinase protein.