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Evaluation of 4‐(4‐Fluorobenzyl)piperazin‐1‐yl]‐Based Compounds as Competitive Tyrosinase Inhibitors Endowed with Antimelanogenic Effects
Author(s) -
Mirabile Salvatore,
Vittorio Serena,
Paola Germanò Maria,
Adornato Ilenia,
Ielo Laura,
Rapisarda Antonio,
Gitto Rosaria,
Pintus Francesca,
Fais Antonella,
De Luca Laura
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100396
Subject(s) - pharmacophore , chemistry , kojic acid , moiety , tyrosinase , stereochemistry , docking (animal) , cytotoxicity , combinatorial chemistry , virtual screening , pharmacology , biochemistry , enzyme , in vitro , biology , medicine , nursing
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 antimelanogenic effect on B16F10 cells in absence of cytotoxicity. Docking analysis suggested its binding mode into AbTYR and into modelled human TYR.