title: An insight into prototropism and supramolecular motifs in solid-state structures of allopurinol, hypoxanthine, xanthine, and uric acid. A ¹H-¹⁴N NQDR spectroscopy, hybrid DFT/QTAIM, and Hirshfeld surface-based study.
abstract: 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 (1)H-(14)N NMR-NQR double resonance. Twelve (14)N 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 (1)H-(14)N 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.
authors: Faculty of Physics, Adam Mickiewicz University , Umultowska 85, 61-614 Poznań, Poland.
authors: Jolanta Natalia
authors: JN
authors: Latosińska
authors: Magdalena
authors: M
authors: Latosińska
authors: Janez
authors: J
authors: Seliger
authors: Veselko
authors: V
authors: Žagar
authors: Zygmunt
authors: Z
authors: Kazimierczuk
mesh_terms: D000493:Allopurinol / Q000737:chemistry* / Q000378:metabolism; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D019271:Hypoxanthine / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D011789:Quantum Theory; D014527:Uric Acid / Q000737:chemistry* / Q000378:metabolism; D019820:Xanthine / Q000737:chemistry* / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019820:Xanthine; D014527:Uric Acid; D019271:Hypoxanthine; D000493:Allopurinol; D006859:Hydrogen; D014969:Xanthine Oxidase; D009584:Nitrogen