Supramolecular self-assembly with p-coumaric acid offers the first cocrystal for perfecting the physicochemical peculiarity and enhancing the antifungal effect of drug bifonazole

Abstract

With the aim of giving prominence to the ability and dominance of phenolic acid nutrient p-coumaric acid (TPA) towards ameliorating the medicinal properties of BCS class-IV antifungal drug bifonazole (BFZ), a cocrystallization-driven tactic for perfecting peculiarity and assisting enhancement efficacy has been put forward. This strategy fully exploits the structural features and property advantages of TPA to lift both the solubility and permeability of the parent drug BFZ through a cocrystallization technique, and at the same time, to heighten the antifungal effect of the drug. Directed by this strategy, a novice cocrystallization complex of BFZ and TPA, namely BFZ–TPA, as the first BFZ cocrystal, is successfully assembled and structurally identified by a variety of analytical means. Single-crystal X-ray diffraction analysis confirms that the BFZ and TPA molecules in the cocrystal are connected through a classical O1–H1A⋯N2 hydrogen-bonding synthon in a stoichiometric ratio of 1 : 1, constructing an intact three-dimensional supramolecular structure. Thereinto, the TPA molecule with a rigid planar structure is filled into the crystal lattice of BFZ via intermolecular interaction, producing a more compact and stable crystal structure landscape. Such a structural trait and accumulation pattern make both the solubility and permeability of BFZ in the cocrystal increased by 3.60- and 2.27-fold in comparison with drug BFZ per se, which can be strongly validated by DFT-based theoretical calculations. Intriguingly, these optimized physicochemical properties significantly enhance the antifungal effect of the cocrystal, exhibiting larger inhibition rings and lower MIC values. Therefore, this work not only contributes a crystalline solid form with a brand-new structure and potential application prospects for BFZ, thus filling the gap of BFZ cocrystal research, but also opens a new application pathway of phenolic acid nutrition in the field of antifungal cocrystal drugs.