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

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 & ctdot;O, N-H & ctdot;O and C-H & ctdot;O hydrogen bonds, also supported by C-H & ctdot;pi 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 & ctdot;pi 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).