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

• DOI: 10.1016/j.ejmech.2019.06.019
• Publication Date: 2019-06-06T11:51:55Z
• Authors: Laura Ielo; Batel Deri; Maria Paola Germanò; Serena Vittorio; Salvatore Mirabile; Rosaria Gitto; Antonio Rapisarda; Simone Ronsisvalle; Sonia Floris; Yael Pazy; Antonella Fais; Ayelet Fishman; Laura De Luca
• Keywords: Kojic acid; Docking (animal); Piperazine; IC50; Lead compound; Structure–activity relationship

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.