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Design, Synthesis, and in Vitro Evaluation of 4‐(4‐Hydroxyphenyl)piperazine‐Based Compounds Targeting Tyrosinase
Author(s) -
Mirabile Salvatore,
Germanò Maria Paola,
Fais Antonella,
Lombardo Lisa,
Ricci Federico,
Floris Sonia,
Cacciola Anna,
Rapisarda Antonio,
Gitto Rosaria,
De Luca Laura
Publication year - 2022
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.202200305
Subject(s) - piperazine , tyrosinase , in vitro , chemistry , combinatorial chemistry , stereochemistry , pharmacology , biochemistry , organic chemistry , biology , enzyme
Melanin biosynthesis is enzymatically regulated by tyrosinase (TYR, EC 1.14.18.1), which is efficiently inhibited by natural and synthetic phenols, demonstrating potential therapeutic application for the treatment of several human diseases. Herein we report the inhibitory effects of a series of (4‐(4‐hydroxyphenyl)piperazin‐1‐yl)arylmethanone derivatives, that were designed, synthesised and assayed against TYR from Agaricus bisporus (AbTYR). The best inhibitory activity was predominantly found for compounds bearing selected hydrophobic ortho ‐substituents on the aroyl moiety (IC 50 values in the range of 1.5–4.6 μM). They proved to be more potent than the reference compound kojic acid (IC 50 =17.8 μM) and displayed competitive mechanism of inhibition of diphenolase activity of AbTYR. Docking simulation predicted their binding mode into the catalytic cavities of AbTYR and the modelled human TYR. In addition, these compounds displayed antioxidant activity combined with no cytotoxicity in MTT tests. Notably, the best inhibitor affected tyrosinase activity in α‐MSH‐stimulated B16F10 cells, thus demonstrating anti‐melanogenic activity.