| Summary: | 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 <b>1</b>, <b>6</b> and <b>7</b> 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 <b>1</b>, <b>6</b> and <b>7</b>, showed values around 80% at 5 µM concentration. In cell proliferation assays, compounds <b>1</b>, <b>6</b> and <b>7</b> 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<sub>50</sub> for compounds <b>1</b>, <b>6</b> and <b>7</b> 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 <b>7</b> 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 H<sub>2</sub>O<sub>2</sub> in amperometric experiments, whereby compound <b>7</b> was about three times more effective compared to compounds <b>1</b> and <b>6</b>. The tyrosinase X-ray structure of <i>Bacterium megaterium</i> crystal was used to carry out molecular docking studies in the presence of compounds <b>1</b>, <b>6</b> and <b>7</b> in comparison with that of kojic acid and arbutin, two conventional tyrosinase inhibitors. Molecular docking of compounds <b>6</b> and <b>7</b> confirmed the high affinity of these compounds to tyrosinase protein.
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