Directed Self-Assembly with Gallic Acid Provides First Phenolic Acid Cocrystals for the Antiviral Drug Acyclovir toward Increasing Pharmaceutical Features and Synergy: A Theoretical and Experimental Integration Research

Abstract

To achieve new breakthroughs in the development of synergistic antiviral medication cocrystals of acyclovir (AYL) with phenolic acids, a cocrystallization-driven strategy for optimizing the physicochemical properties and increasing the antiviral efficacy is proposed. This method emphasizes the structural features and medicinal value together with the dominant properties of gallic acid (GLA) to promote both solubility and permeability of AYL by cocrystallizing GLA into AYL's lattice; meanwhile, the antiviral ability of ALY can be greatly increased by activating the antiviral potential of GLA and utilizing the synergistic antiviral activity of both in cocrystal formation. Guided by this idea, the first AYL-phenolic acid cocrystal, AYL-GLA-2H 2 O, is orientationally constructed and fully characterized. The accurate cocrystal structure revealed by single-crystal X-ray diffraction indicates that the entry of GLA into the AYL lattice has disrupted the homodimer of AYL itself, leading to the formation of a hydrophobic heterodimer between AYL and GLA molecules, coupled with an aqueous tetramer, thus endowing the cocrystal with both hydrophilic and hydrophobic characteristics. Such structural feature induces a concurrent enhancement in dissolubility and permeability of the cocrystal compared with the parent medicine. These observations can be strongly supported by density functional theory-based theoretical investigations involving molecular electrostatic potential, Hirshfeld surface, frontier molecular orbital, and Gibbs solvation free energy. Interestingly, the perfected AYL's properties along with the stimulated antiviral activity of GLA enable the two ingredients in the cocrystal to display synergistic antiviral activity against the herpes simplex virus with a cooperativity index of less than 1, contributing to enhancing the antiviral ability. Thus, this contribution not only highlights the effectiveness of combining theory with experiment to solve AYL's issues via the cocrystallization-driven method but fills in the gaps from previous studies on AYL-phenolic acid cocrystals with synergistic antiviral effects.

Simultaneous Enhancement of Thermal Stability and Preferred Isomer Enrichment in Difenoconazole: the Dual Facets of Cocrystal Engineering

“…MEPs, a highly efficient and universally recognized quantum-molecular descriptor, play a pivotal role in pinpointing the most critical reactive sites within molecular structures, delineating the electrophilic and nucleophilic regions. − In cocrystals, MEPs can help in identifying regions of positive, negative, and neutral electrostatic potential on the molecular surface, which is essential for understanding how the components of a cocrystal might interact with each other. , Red areas indicate positive electrostatic potential, serving as donor probes, while blue areas represent negative electrostatic potential, acting as acceptor probes.…”

“…Molecular interactions within the crystal structures were quantified and visualized through Hirshfeld surface analysis and 2D fingerprint plots, utilizing the Crystal Explorer 21.5 . Density Functional Theory (DFT) optimization calculations were performed using the Gaussian 16 software, employing the B3LYP functional and the 6-311G­(d,p) basis set. , Data regarding the frontier molecular orbitals (FMOs) and molecular electrostatic potential surface (MEPs) were acquired through the Multiwfn analytical procedure and visualized with the visual molecular dynamics (VMD) program …”

Gefitinib salts/cocrystals with phenolic acids as a promising solid-state approach to improve solubility

“…27 Salt and/or cocrystal formation represents a potential strategy for improving the physical and chemical properties of GEF. Characterized by their good solubility and permeability, low toxicity, and reliable safety, phenolic acids have been recognized as a class of potential efficient cocrystal formers (CCFs) for enhancing the poor physicochemical properties of active pharmaceutical ingredients (APIs), such as ketoconazole, 28 milrinone, 29 amantadine hydrochloride, 30 acyclovir, 31 temozolomide, 32 ambrisentan, 33 and voriconazole. 34 The carboxyl and hydroxy groups on the phenolic acid molecular skeleton serve as excellent acceptors and/or donors of hydrogen bonding synthons, facilitating the formation of various intermolecular interactions and creating favorable conditions for self-assembly.…”