Synthesis, molecular modeling, quantum chemical calculations and in silico drug profiling of the novel (4-phenylpiperazin-1-ium) hydrogenfumarate as a tyrosinase inhibitor

Mahdi Jemai , Noureddine Issaoui EMAIL logo , Thierry Roisnel , Aleksandr S. Kazachenko , Houda Marouani and Omar M. Al-Dossary// Zeitschrift für Physikalische Chemie//

The complexation between fumaric acid (FA) and 1-phenylpiperazine (1 PP) is a fruitful cooperation that allowed the preparation of a new organic crystal entitled (4-phenylpiperazin-1-ium) hydrogenfumarate denoted by 4PPHFUM, which is reported in the present manuscript. This new substance is created by the slow evaporation that occurs when 1-phenylpiperazine and fumaric acid are combined in a stoichiometric 1:1 ratio. The stacking of the crystal is provided by O–H⋯O, N–H⋯O and C–H⋯O hydrogen bonds, also supported by C–H⋯π interactions between the organic cations. The importance of these interactions in the formation of this new crystal is confirmed by the Hirshfeld surface analysis which showed that H-bonds and supramolecular C–H⋯π interactions account for about half of the non-covalent interactions existing in this compound. These non-covalent bonds that encompass the synthesis and design of this supramolecule have also been analyzed in detail using a quantum chemical computational study. Using the docking – based drug design strategy, we investigated the therapeutic effect of this cooperative outcome between fumaric acid and 1-phenylpiperazine to demonstrate the improved therapeutic property of this novel non-covalent compound as a tyrosinase inhibitor. 4PPHFUM was found to be a potent tyrosinase inhibitor with high interaction energy with its protein, higher than that of the most potent tyrosinase inhibitors (thiamidol, hydroquinone, resorcinol, hexylresorcinol and kojic acid).