4-Fluorobenzylpiperazine-Containing Derivatives as Efficient Inhibitors of Mushroom Tyrosinase.

Tyrosinase is a type-3 copper protein involved in the biosynthesis of melanin pigments; therefore, the inhibition of its enzymatic activity represents a promising strategy for the treatment of hyperpigmentation-related disorders. To address this point, we previously designed a class of 4-(4-fluorobenzyl)piperazin-1-yl-based compounds, which proved to be more active inhibitors against tyrosinase from mushroom Agaricus bisporus than the positive control kojic acid. Herein, we report the synthesis of further series of 4-(4-fluorobenzyl)piperazin-1-yl analogues bearing a (hetero)aromatic fragment as key feature to improve protein affinity. The newly synthesized compounds were assayed in vitro and proved to be potent inhibitors in the low-micromolar range. The active 2-thienyl and 2-furyl derivatives were selected for further modification to allow their binding mode to be analyzed by docking studies and to give satisfactory safety profiles.