Salts of purine alkaloids caffeine and theobromine with 2,6-dihydroxybenzoic acid as coformer: structural, theoretical, thermal and spectroscopic studies.

The study of various forms of pharmaceutical substances with specific physicochemical properties suitable for putting them on the market is one of the elements of research in the pharmaceutical industry. A large proportion of active pharmaceutical ingredients (APIs) occur in the salt form. The use of an acidic coformer with a given structure and a suitable pKa value towards purine alkaloids containing a basic imidazole N atom can lead to salt formation. In this work, 2,6-dihydroxybenzoic acid (26DHBA) was used for cocrystallization of theobromine (TBR) and caffeine (CAF). Two novel salts, namely, theobrominium 2,6-dihydroxybenzoate, C7H9N4O2+·C7H5O4- (I), and caffeinium 2,6-dihydroxybenzoate, C8H11N4O2+·C7H5O4- (II), were synthesized. Both salts were obtained independently by slow evaporation from solution, by neat grinding and also by microwave-assisted slurry cocrystallization. Powder X-ray diffraction measurements proved the formation of the new substances. Single-crystal X-ray diffraction studies confirmed proton transfer between the given alkaloid and 26DHBA, and the formation of N-H...O hydrogen bonds in both I and II. Unlike the caffeine cations in II, the theobromine cations in I are paired by noncovalent N-H...O=C interactions and a cyclic array is observed. As expected, the two hydroxy groups in the 26DHBA anion in both salts are involved in two intramolecular O-H...O hydrogen bonds. C-H...O and π-π interactions further stabilize the crystal structures of both compounds. Steady-state UV-Vis spectroscopy showed changes in the water solubility of xanthines after ionizable complex formation. The obtained salts I and II were also characterized by theoretical calculations, Fourier-transform IR spectroscopy (FT-IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and elemental analysis.

Synthesis, structure and biological evaluation of novel bicyclic nitroimidazole derivatives.

A new series of 3-hydroxy-8-nitroimidazo[5,1-b]-1,4,5,6-tetrahydropyrimidine systems, being potential tuberculostatic agents, were synthesized. These products are close structural analogs of the basic structure of the known antitubercular bicyclic nitroimidazooxazine PA-824. The structures of the products obtained were confirmed by X-ray methods on the example of 3-hydroxy-8-nitro-1-phenylaminoimidazo[5,1-b]-1,4,5,6-tetrahydropyrimidine. Evaluation of these products for their anti-tuberculosis effects revealed interesting structure-activity relationships.

5-Ethynyl-1-ß-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (ETCAR) and its analogues: synthesis and cytotoxic properties.

Efficient Pd(0)-catalysed synthesis of 5-alkynyl-1-ß-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide depends on the presence of different protecting groups of the ribose moiety. Peracetylated 5-iodo substrate (15) couples with terminal alkynes or trimethyl-[(tributylstannyl)ethynyl]silane in 50-71% and 72% yield (ETCAR), respectively, although its hydrodehalogenation to 19 is noticeable. On the other hand, hydrodehalogenation of acetonide (16) predominates over coupling with terminal alkyne and slightly decreases a yield of cross-coupling reaction with trimethyl[(tributylstannyl)ethynyl]silane. Alternative conditions of reaction with terminal alkynes, to exclude so far identified hydride sources to produce hydridopalladium species, have been established for acetonide 16 and allowed to achieve 72% of coupling. Fluoromethyl derivative (42) was prepared from its 5-hydroxymethyl precursor by fluorination with DAST. Additionally, X-ray structural analysis of 42 was performed. All 1,2,3-triazolonucleosides and two synthesized cycloSal-pronucleotides were evaluated for cytotoxic activity against K562, HeLa and HUVEC cells.

Structure and dynamics of L-selenomethionine in the solid state.

L-selenomethionine 1 crystallizes in P2(1) space group with two molecules in the asymmetric unit. Solid-state NMR spectroscopy is used for searching of structure and dynamics of 1 in the crystal lattice. The distinct molecular motion of side chains for A and B molecules of 1 is apparent from measurements of relaxation parameters (1H 1rho, 13C T1) and analysis of CSA data (2D-PASS experiment). The 13C delta(ii) and 77Se delta(ii) parameters are correlated with theoretical shielding parameters obtained by means DFT GIAO calculations. Attempt to explain the mechanism of phase transition of crystals of 1 at 313K is presented.

Improper hydrogen C-H...O bonds cause self-association of alpha, beta-enaminoketones containing fluorosubstituted alkyl groups.

Concentration- and temperature-dependent IR, NMR and dipole-moment studies on 4-N,N-dimethylamino-1,1,1-trifluoro-3-buten-2-one and two of its higher homologues showed that these compounds undergo reversible dimerization in nonpolar solvents. Antiparallel "closed" dimers are formed with a network of improper intermolecular C-H...O hydrogen bonds. Quantitative analysis of the 1H NMR data yielded delta H0 = -17.6 kJ mol-1 and delta S0 = -46.9 J deg-1 mol-1. The interactions observed are the strongest among those involving a C-H group reported so far. The complex described here is the first example of a cyclic complex stabilized by two improper C-H...O hydrogen bonds. The conclusions drawn from the solution and solid-state data were confirmed by ab initio calculations.