Evaluation of novel 4-(4-fluorobenzyl)piperazin-1-yl]-based compounds as competitive tyrosinase inhibitors endowed with anti-melanogenic effects

Mirabile, Salvatore;Vittorio, Serena;Germanò, Maria Paola;Adornato, Ilenia;Ielo, Laura;Rapisarda, Antonio;Gitto, Rosaria;Pintus, Francesca;De Luca, Laura;Fais, Antonella

2021-01-01

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Abstract

There is a considerable attention for the development of inhibitors of tyrosinase (TYR) as therapeutic strategy for the treatment of hyperpigmentation disorders in humans. Continuing in our efforts to identify TYR inhibitors, we describe the design, synthesis and pharmacophore exploration of new small molecules structurally characterized by the presence of the 4-fluorobenzylpiperazine moiety as key pharmacophoric feature for the inhibition of TYR from  Agaricus bisporus (AbTYR). Our investigations resulted in the discovery of the competitive inhibitor [4-(4-fluorobenzyl)piperazin-1-yl]-(3-chloro-2-nitro-phenyl)methanone 26 (IC 50  = 0.18 μM) that proved to be ∼100-fold more active than reference compound kojic acid (IC 50  = 17.76 μM). Notably, compound 26 exerted anti-melanogenic effect on B16F10 cells in absence of cytotoxicity. Docking analysis suggested its binding mode into AbTYR and into modelled human TYR.