A DFT study on the structure activity relationship of the natural xanthotoxin-based pharmaceutical cocrystals.

In this work, the pharmaceutical cocrystals xanthotoxin-para-aminobenzoic acid (XT-PABA) and xanthotoxin-oxalic acid (XT-OA) were systematically investigated in the gas and water phases by using the quantum chemical approach. The weak intermolecular interactions have been estimated and the O1…H4 (O1…H5) intermolecular hydrogen bond (IHB) with moderate intensity and partial covalent natures was confirmed based on the computed structural parameters, topology analysis, and reduced density gradient (RDG) isosurfaces. The electrophilic and nucleophilic reactivities of different positions associated with intermolecular interactions in XT, PABA, and OA were predicted by plotting the molecular electrostatic potential (MESP) diagrams. The calculated natural bond orbital (NBO) population analysis has quantitatively unveiled the intrinsic reason for the variations in weak intermolecular interactions within XT-PABA and XT-OA cocrystals, from the gas phase to the water phase. Besides, the frontier molecular orbitals (FMOs), Fukui function, and various global reactivity descriptors were computed to measure the chemical reactivity of all the investigated molecular systems. The XT-PABA and XT-OA cocrystals explored in this work could be regarded as valuable exemplar systems to design and synthesize the high-efficiency pharmaceutical cocrystals in the experiment.