The current work aims to take full advantage of the structural superiority and hepatoprotective effect of nutriment trans-p-coumaric acid (TPCA) to decrease the solubility and dissolution rate of antimycotic agent 5-fluorocytosine (FLCY) by co-crystallization strategie, thereby giving a novel understanding into conquering dose-limiting hepatotoxicity induced by quick and almost complete absorption of FLCY. Toward that end, FLCY-TPCA, as the first cocrystal of FLCY with phenolic acid nutriment of hydroxycinnamic acid types, is orientationally self-assembled and fully characterized. The single crystal structure identifies that TPCA molecules in the crystal lattice capture the polar sites in situ of FLCY via robust hydrogen bond interplays, thus creating a vital planar construction (VPC) possessing hydrophobe feature, which results in the simultaneous down-regulation for the cocrystal in solubility and dissolution rate versus parent FLCY. The outcomes of the experiment are forcefully supported by related theory researches. Molecular electrostatic potential (MEP) calculation manifests that the VPC polarity in the cocrystal is lower than that of free FLCY, which conforms with the reduction in polarity due to intensifying hydrogen-bonds energy based on topology analysis with atoms in molecules (AIM) theory, hence conferring a conspicuous improvement in hydrophobicity on the cocrystal. Furthermore, the molecular planarity analysis on account of Multiwfn’s wave function calculation module confirms the convergence in planarity at a two-dimensional infinite level, which undoubtedly contributes to accomplishing a tight three-dimensional supramolecular superposition landscape, corresponding with the coinstantaneous reinforcement of π-π stacking interaction analyzed by the reduced density gradient (RDG), and all these further support the fact that the hydrophobicity of FLCY-TPCA cocrystal is significantly enhanced. As a result, the current contribution exemplifies the feasible cocrystallization clues by integrated experimental with systematic theoretical approaches to overcoming intractable toxicity issues of antifungal agents.

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