Michał Sowa

Cocrystals of fisetin, luteolin and genistein with pyridinecarboxamide coformers: crystal structures, analysis of intermolecular interactions, spectral and thermal characterization

Fisetin, luteolin and genistein, natural polyphenolic compounds of pharmaceutical interest, were combined with nicotinamide and isonicotinamide with an aim to obtain their cocrystals. A screening experiment utilizing solvent-drop grinding was conducted for those combinations. Cocrystalline phases were identified by XRPD and, as far as possible, obtained as single crystals in solution evaporation approach. Five new cocrystals were isolated, characterized by X-ray single-crystal diffraction, FT-Raman spectroscopy, thermal analysis (DSC and TG–DTA), 1H NMR in solution and compared in terms of supramolecular motifs. Reported herein fisetin–nicotinamide (1 : 2) ethanol hemisolvate (FisNam), fisetin–isonicotinamide (1 : 1) (FisInam), two polymorphic forms of luteolin–isonicotinamide (1 : 1) (LutInam, LutInam2) and genistein–nicotinamide (1 : 1) monohydrate (GenNam) cocrystals reveal the presence of an O–H⋯Narom heterosynthon between an O7 hydroxyl moiety of a flavonoid and the pyridyl ring of a coformer. Within those species, mutual orientations of molecules as well as flavonoid–coformer stoichiometry and solvent presence in crystal lattice are factors that imply resulting motif formation and crystal packing.

A 1:1 cocrystal of baicalein with nicotinamide.

Cocrystallization of baicalein with nicotinamide yields a 1:1 cocrystal [systematic name: pyridine-3-carboxamide-5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one (1/1)], C(6)H(6)N(2)O·C(15)H(10)O(5). The asymmetric unit contains one baicalein and one nicotinamide molecule, both in neutral forms. Molecules in the cocrystal form column motifs stabilized by an array of intermolecular hydrogen bonds.

Improving solubility of fisetin by cocrystallization

Fisetin, a naturally occurring polyphenolic compound, has a proven record of in vitro demonstrated anti-carcinogenic, anti-inflammatory and antiviral properties, yet similarly to many promising APIs, its in vivo administration is complicated by low aqueous solubility and unfavourable pharmacokinetics. The presented study was focused on obtaining and characterizing cocrystals of fisetin, with the aim of improving its solubility. Solvent-drop grinding experiments, combined with FT-Raman and XRPD, were conducted to identify new cocrystalline phases, which were afterwards isolated as single-crystals and characterized structurally and in terms of thermal stability and solubility. Dissolution studies of pure fisetin and four cocrystals, namely fisetin–isonicotinamide 1 : 1 (FisInam), fisetin–nicotinamide 1 : 2 hemiethanolate (FisNam), fisetin–nicotinamide 1 : 1 (FisNam2) and fisetin–caffeine 1 : 2 (FisCaf), showed that a 2.5-fold increase of fisetin solubility was achieved for FisNam and to a smaller extent for FisCaf and FisInam (ca. 1.8- and 1.5-fold, respectively).

A 1:2 cocrystal of genistein with isonicotinamide: crystal structure and Hirshfeld surface analysis.

Genistein, a naturally occurring polyphenolic compound, was combined with isonicotinamide, a pharmaceutically acceptable coformer, to yield a 1:2 cocrystal [systematic name: 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one-pyridine-4-carboxamide (1/2)], C15H10O5·2C6H6N2O. The molecules in the cocrystalline phase are present in their neutral forms, and assemble a molecular layer by means of hydrogen bonding.

Zinc(II) complexes derived from imidazo[1,2-a]pyridin-2-ylacetic acid (HIP-2-ac): [Zn(IP-2-ac)2(H2O)] and unexpectedly, [Zn3(IP-2-ac)6(H2O)]·11H2O

Two zinc(II) complexes based on imidazo[1,2-a]pyridin-2-ylacetate (IP-2-ac), [Zn(IP-2-ac)2(H2O)] (1) and [Zn3(IP-2-ac)6(H2O)]·11H2O (2), were synthesized and characterized by single-crystal X-ray diffraction. In both 1 and 2, zinc(II) ions are five-coordinate with N2O3 donor set, best described as a distorted trigonal-bipyramidal geometry. In 1, two IP-2-ac ligands chelate zinc(II) through a N,O donor set, whereas in 2, both bidentate and μ-bridging binding modes of IP-2-ac are observed. The crystal of 1 comprises discrete Zn(IP-2-ac)2(H2O) coordination entities combined into layers by hydrogen bonds. Inter-layer stabilization of the 3-D crystal lattice is provided by weak C–H⋯O contacts and π⋯π interactions. The structure of 2 consists of discrete trinuclear Zn3(IP-2-ac)6(H2O) coordination entities joined into crystal lattice by multiple water molecules. Compound 1 was characterized by FTIR and FT-Raman spectroscopy, and in terms of thermal stability. Furthermore, its antibacterial activity was tested against selected gram-positive, gram-negative bacteria, and Candida albicans yeast and compared with activity of previously reported [M(IP-2-ac)2(H2O)2]·2H2O (M = Co, Ni, Mn, Cd) complexes. Graphical abstract

Silver(I) complex with 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazin-3-one (Phx-1) ligand: crystal structure, vibrational spectra and biological studies

Abstract The first metal complex of Phx-1 ligand, bis(2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazin-3-one)nitratosilver(I), [Ag(Phx-1)2NO3], has been obtained and investigated by single crystal X-ray diffraction and vibrational spectroscopy methods. The Ag+ is bonded to heterocyclic nitrogen atoms of two organic ligands and one oxygen atom of a nitrate anion. The Phx-1 ligand coordination mode is supported by IR and Raman spectra, interpreted with the help of theoretical DFT studies. The antibacterial activity of the ligand and its Ag(I) complex as well as some reference compounds were screened against Gram-positive and Gram-negative bacteria, applying microdilution procedures. High sensitivity to the studied complex was found for Rhodococcus erythropolis and Bacillus licheniformis strains. Modified Phx-1 ligand preparation procedures are also presented.