LAUSR

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.