Evaluation of 4-(4-Fluorobenzyl)piperazin-1-yl]-Based Compounds as Competitive Tyrosinase Inhibitors Endowed with Antimelanogenic Effects
| Autor: | Laura Ielo, Francesca Pintus, Serena Vittorio, Rosaria Gitto, Maria Paola Germanò, Ilenia Adornato, Laura De Luca, Antonio Rapisarda, Antonella Fais, Salvatore Mirabile |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
Tyrosinase Agaricus Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Synthesis Drug Discovery Tumor Cells Cultured Moiety Animals Humans Tyrosinase inhibitors Docking studies General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors Cytotoxicity IC50 Piperazine Pharmacology Homology model Kinetic mechanism Dose-Response Relationship Drug Molecular Structure Full Paper Monophenol Monooxygenase Organic Chemistry Full Papers Small molecule Molecular Docking Simulation chemistry Docking (molecular) Molecular Medicine Pharmacophore Kojic acid |
| Zdroj: | Chemmedchem |
| Popis: | 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 (IC50=0.18 μM) that proved to be ∼100‐fold more active than reference compound kojic acid (IC50=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. The design, synthesis, and pharmacophore exploration of new molecules structurally characterized by the 4‐fluorobenzylpiperazine fragment are reported. Their inhibitory effects on Agaricus bisporus tyrosinase (AbTYR) were evaluated. Notably, the competitive derivative 26 revealed no cytotoxicity and exerted antimelanogenic effects on B16F10 cells. Docking analysis suggested its binding mode into AbTYR and into modelled human TYR. |
| Databáze: | OpenAIRE |
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