An Insight into Prototropism and Supramolecular Motifs in Solid-State Structures of Allopurinol, Hypoxanthine, Xanthine, and Uric Acid. A H-1-N-14 NQDR Spectroscopy, Hybrid DFT/QTAIM, and Hirshfeld Surface-Based Study

作者：Latosinska Jolanta Natalia^*; Latosinska Magdalena; Seliger Janez; Zagar Veselko; Kazimierczuk Zygmunt

来源：Journal of Physical Chemistry B, 2014, 118(37): 10837-10853.

DOI：10.1021/jp504871y

Allopurinol (1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one), the active pharmaceutical ingredient (API) of the drugs applied for the treatment of gout and tumor lysis syndrome, recently discovered to have multifaceted therapeutic potential, and hypoxanthine which is a naturally occurring purine have been studied experimentally in the solid state by H-1-N-14 NMR-NQR double resonance. Twelve N-14 resonance frequencies have been detected at 295 K and assigned to two pairs of two kinds of nitrogen sites (-N=. and -NH) in each compound. The experimental results are supported by and interpreted with the help of quantum theory of atoms in molecules (QTAIM)/density functional theory (DFT) calculations. The factors, such as the substituent effect, in particular the shift of nitrogen from position 7 (as in hypoxanthine) to position 8 (as in allopurinol), hybridization, possible prototropic tautomerism, and the pattern of intermolecular bonding, have been taken into account in H-1-N-14 NMR-NQR spectra interpretation. This study demonstrates the advantages of combining NQR, DFT/QTAIM, and Hirshfeld surface analysis to extract detailed information on electron density distribution and complex H-bonding networks in crystals of purinic type heterocycles, relevant in pharmacological processes. In the absence of X-ray data for xanthine, the NQR parameters supported by DFT/QTAIM calculations and Hirshfeld surface analysis were proved to be valuable tools for clarifying the details of crystalline packing and predicting an unsolved crystalline structure of xanthine. The influence of a decrease in purine ring conjugation level upon oxidation on the biological activity of allopurinol, a xanthine oxidase (XO) enzyme inhibitor, which blocks the conversion of hypoxanthine to xanthine and subsequently xanthine to uric acid, is also discussed.

• 出版日期2014-9-18