Exploiting the 1-(4-fluorobenzyl)piperazine fragment for the development of novel tyrosinase inhibitors as anti-melanogenic agents: Design, synthesis, structural insights and biological profile

Autor: Antonio Rapisarda, Laura De Luca, Sonia Floris, Yael Pazy, Antonella Fais, Maria Paola Germanò, Batel Deri, Ayelet Fishman, Serena Vittorio, Rosaria Gitto, Salvatore Mirabile, Laura Ielo, Simone Ronsisvalle
Rok vydání: 2019
Předmět:
Models
Molecular
Agaricus
Tyrosinase
Crystallography
X-Ray
Drug Screening Assays
01 natural sciences
Piperazines
B16F10 melanoma cells
Melanin
chemistry.chemical_compound
Models
Drug Discovery
Docking studies
Enzyme Inhibitors
Cytotoxicity
chemistry.chemical_classification
0303 health sciences
anti-melanogenic effects
Tyrosinase inhibitors
X-ray crystallography
Antineoplastic Agents
Cell Line
Tumor
Cell Proliferation
Dose-Response Relationship
Drug
Drug Screening Assays
Antitumor
Humans
Molecular Structure
Monophenol Monooxygenase
Structure-Activity Relationship
Drug Design
Tumor
Crystallography
General Medicine
Biochemistry
Drug
In silico
Cell Line
Dose-Response Relationship
03 medical and health sciences
Oxidoreductase
030304 developmental biology
Pharmacology
010405 organic chemistry
Organic Chemistry
Molecular
Antitumor
0104 chemical sciences
Piperazine
chemistry
Design synthesis
X-Ray
Kojic acid
anti-melanogenic effects
B16F10 melanoma cells
Docking studies
Tyrosinase inhibitors
X-ray crystallography
Zdroj: European Journal of Medicinal Chemistry. 178:380-389
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2019.06.019
Popis: The development of Tyrosinase inhibitors (TYRIs) could represent an efficacious strategy for pharmacological intervention on skin pathologies related to aberrant production of melanin. Based on in silico studies we designed and tested a library of twenty-four compounds bearing the 4-(4-fluorobenzyl)piperazin-1-yl]-fragment. As result, we identified several compounds with excellent inhibit effects at low micromolar concentration against TYR from Agaricus bisporus (TyM). Among them, compound 25 (IC50 = 0.96 μM) proved to be ∼20-fold more potent than the reference compound kojic acid (IC50 = 17.76 μM) having wide applications in the cosmetics and pharmaceutical industries. The mode of interaction of active inhibitor 25 was deciphered by means of crystallography as well as molecular docking and these results were consistent with kinetic experiments. Moreover, the identified compound 25 exhibited no considerable cytotoxicity and showed anti-melanogenic effects on B16F10 melanoma cells. Therefore, a combination of computational and biochemical approaches could represent a rational guidelines for further structural modification of this class of compounds as future anti-melanogenic agents.
Databáze: OpenAIRE
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