Tyrosinase enzymes (Tys) are involved in the key steps of melanin (protective pigments) biosynthesis and molecules targeting the binuclear copper active site on tyrosinases represent a relevant strategy to regulate enzyme activities. In this work, the possible synergic effect generated by a combination of known inhibitors is studied. For this, derivatives containing kojic acid (KA) and 2‐hydroxypyridine‐N‐oxide (HOPNO) combined with a thiosemicarbazone (TSC) moiety were synthetized. Their inhibition activities were evaluated on purified tyrosinases from different sources (mushroom, bacterial, and human) as well as on melanin production by lysates from the human melanoma MNT‐1 cell line. Results showed significant enhancement of the inhibitory effects compared with the parent compounds, in particular for HOPNO‐TSC. To elucidate the interaction mode with the dicopper(II) active site, binding studies with a tyrosinase bio‐inspired model of the dicopper(II) center were investigated. The structure of the isolated adduct between one ditopic inhibitor (KA‐TSC) and the model complex reveals that the binding to a dicopper center can occur with both chelating sites. Computational studies on model complexes and docking studies on enzymes led to the identification of KA and HOPNO moieties as interacting groups with the dicopper active site.

The role of reagents NaBH4/MeOH and nickel boride (Ni2B) generated in situ from NaBH4 and NiCl2, are compared in the reduction process of coumarin and a variety of 3,7‐substituted coumarins bearing electro‐donating (ED‐group) or electro‐withdrawing groups (EW‐group). Coumarins (chromen‐2‐ones) are only reduced by Ni2B to the cyclic chromanones. This provides a useful and very simple reduction method for electron‐rich coumarins, which are resistant to many other reducing methods. DFT calculations underlined the role of substituents electronic effects in the reactivity. Subsequent methanolysis may open the ring to methyl phenylpropanoate esters and alcohols resulting from their reductions can also be produced.

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