New Polymorphic Modifications of 6-Methyluracil: An Experimental and Quantum Chemical Study.

Polymorphism of 6-methyluracil, which affects the regulation of lipid peroxidation and wound healing, has been studied by experimental and quantum chemical methods. Two known polymorphic modifications and two new crystalline forms were crystallized and characterized by single crystal and powder X-ray diffraction (XRD) methods as well as by the differential scanning calorimetry (DSC) method and infrared (IR) spectroscopy. The calculations of pairwise interaction energies between molecules and lattice energies in periodic boundary conditions have shown that the polymorphic form 6MU_I used in the pharmaceutical industry and two new forms 6MU_III and 6MU_IV, which can be formed due to temperature violations, may be considered as metastable. The centrosymmetric dimer bound by two N-H···O hydrogen bonds was recognized as a dimeric building unit in all of the polymorphic forms of 6-methyluracil. Four polymorphic forms have a layered structure from the viewpoint of interaction energies between dimeric building units. The layers parallel to the (100) crystallographic plane were recognized as a basic structural motif in the 6MU_I, 6MU_III, and 6MU_IV crystals. In the 6MU_II structure, a basic structural motif is a layer parallel to the (001) crystallographic plane. The ratio between the interaction energies within the basic structural motif and between neighboring layers correlates with the relative stability of the studied polymorphic forms. The most stable polymorphic form 6MU_II has the most anisotropic "energetic" structure, while the interaction energies in the least stable form 6MU_IV are very close in various directions. The modeling of shear deformations of layers in the metastable polymorphic structures has not revealed any possibility of these crystals to be deformed under external mechanical stress or pressure influence. These results allow the use of metastable polymorphic forms of 6-methyluracil in the pharmaceutical industry without any limitations.

4-[(Benzyl-amino)-carbon-yl]-1-methyl-pyridinium bromide hemihydrate: X-ray diffraction study and Hirshfeld surface analysis.

The hemihydrate of 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium bromide, C14H15N2O+·Br-·0.5H2O, was studied by single-crystal and powder X-ray diffraction methods. In the asymmetric unit, two organic cations of similar conformation, two bromide anions and one water mol-ecule are present. In the crystal, N-H⋯Br hydrogen bonds link the cations and anions. The formation of a set of inter-molecular C-H⋯Br and C-H⋯π inter-actions result in double chains extending parallel to [011]. A Hirshfeld surface analysis showed high contributions of H⋯H and C⋯H/H⋯C short contacts to the total Hirshfeld surfaces of the cations.

4-[(Benzyl-amino)-carbon-yl]-1-methyl-pyridinium halogenide salts: X-ray diffraction study and Hirshfeld surface analysis.

Two salts of 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium (Am) with chloride (C14H15N2O+·Cl-) and bromide (C14H15N2O+·Br-) anions were studied and compared with the iodide salt. AmCl crystallizes in the centrosymmetric space group P21/n while AmBr and AmI form crystals in the Sohncke space group P212121. Crystals of AmBr are isostructural to those of AmI. The cation and anion are bound by an N-H⋯Hal hydrogen bond. Hirshfeld surface analysis was used to compare different types of inter-molecular inter-actions in the three structures under study.

Salts of 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium and iodide anions with different cation:iodine stoichiometric ratios.

The two iodide salts, 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium iodide-iodine (2/1), C14H15N2O+·I-·0.5I2, I, and 4-[(benzyl-amino)-carbon-yl]-1-methyl-pyridinium triiodide, C14H15N2O+·I3 -, II, with different cation:iodine atoms ratios were studied. Salt I contains one cation, one iodide anion and half of the neutral I2 mol-ecule in the asymmetric unit (cation:iodine atoms ratio is 1:2). Salt II contains two cations, one triiodide anion (I 3 -) and two half triiodide anions (cation:iodine atoms ratio is 1:3). The NH group forms N-H⋯I hydrogen bonds with the I- anion in the crystal of I or N-H⋯O hydrogen bonds in II where only triiodide anions are present.

Synthesis, anticancer activity, and molecular modeling of 1,4-naphthoquinones that inhibit MKK7 and Cdc25.

Cell division cycle 25 (Cdc25) and mitogen-activated protein kinase kinase 7 (MKK7) are enzymes involved in intracellular signaling but can also contribute to tumorigenesis. We synthesized and characterized the biological activity of 1,4-naphthoquinones structurally similar to reported Cdc25 and(or) MKK7 inhibitors with anticancer activity. Compound 7 (3-[(1,4-dioxonaphthalen-2-yl)sulfanyl]propanoic acid) exhibited high binding affinity for MKK7 (Kd = 230 nM), which was greater than the affinity of NSC 95397 (Kd = 1.1 µM). Although plumbagin had a lower binding affinity for MKK7, this compound and sulfur-containing derivatives 4 and 6-8 were potent inhibitors of Cdc25A and Cdc25B. Derivative 22e containing a phenylamino side chain was selective for MKK7 versus MKK4 and Cdc25 A/B, and its isomer 22f was a selective inhibitor of Cdc25 A/B. Docking studies performed on several naphthoquinones highlighted interesting aspects concerning the molecule orientation and hydrogen bonding interactions, which could help to explain the activity of the compounds toward MKK7 and Cdc25B. The most potent naphthoquinone-based inhibitors of MKK7 and/or Cdc25 A/B were also screened for their cytotoxicity against nine cancer cell lines and primary human mononuclear cells, and a correlation was found between Cdc25 A/B inhibitory activity and cytotoxicity of the compounds. Quantum chemical calculations using BP86 and ωB97X-D3 functionals were performed on 20 naphthoquinone derivatives to obtain a set of molecular electronic properties and to correlate these properties with cytotoxic activities. Systematic theoretical DFT calculations with subsequent correlation analysis indicated that energy of the lowest unoccupied molecular orbital E(LUMO), vertical electron affinity (VEA), and reactivity index ω of these molecules were important characteristics related to their cytotoxicity. The reactivity index ω was also a key characteristic related to Cdc25 A/B phosphatase inhibitory activity. Thus, 1,4-naphthoquinones displaying sulfur-containing and phenylamino side chains with additional polar groups could be successfully utilized for further development of efficacious Cdc25 A/B and MKK7 inhibitors with anticancer activity.

Aminoalkoxyfluorenones and aminoalkoxybiphenyls: DNA binding modes.

Many evidences suggest that DNA-drug interaction in the minor groove and the intercalation of drugs into DNA may play critical roles in antiviral, antimicrobial, and antitumor activities. As a continuous effort to develop novel antiviral agents, the series of planar fluorenone (3a-7d) were synthesized and used along with nonplanar biphenyls (11a-d) for the comparative analysis of their interaction with DNA. The chemical structure of new compounds was confirmed by 1H NMR, 13C NMR and mass spectra as well as elemental analysis. DNA affinity of 3a-7d and 11a-d was evaluated by ethidium bromide displacement assay. Affinity constant (lgKa) of 3a-7d was found to be approximately two orders of magnitude higher than constants of corresponding 11a-d. The molecular docking of aminoalkoxybiphenyls (11a-d) into minor grove of five different nucleotide sequences (d(CCIICICCII), d(CGCGTTAACGCG), d(CGCGATATCGCG), d(GGCCAATTGG), d(GGATATATCC)) demonstrated their binding capacity to the specific DNA site. The linear least squares fitting technique was successfully applied to derive an equation describing the relationship between lgKa and SF.

Polymorphic modifications of a 1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide possessing strong diuretic properties.

6-Hydroxy-N-(4-methoxyphenyl)-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, C19H16N2O4, possesses strong diuretic properties and can be used as a new hypertension remedy. Two polymorphic modifications of this compound have been found, namely the triclinic polymorph (space group P-1), with one molecule in the asymmetric unit, and the monoclinic polymorph (space group P21/n), with two molecules in asymmetric unit. An analysis of the pairwise interaction energies between the molecules in the crystal phase revealed differences in the crystal packing. The triclinic form has only one level of organization, namely a chain/column, while the monoclinic form has two levels of organization, with a chain/column as the primary basic structural motif and a layer as the secondary basic structural motif.

Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents.

This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations.

Conformationally restricted GABA analogs: from rigid carbocycles to cage hydrocarbons.

GABA was discovered to play an important role as the major inhibitory neurotransmitter in the adult mammalian CNS 60 years ago. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. In an effort to increase the lipophilicity and to reduce conformational flexibility of GABA itself, a polycyclic or cage hydrocarbon framework can be introduced into the 3D structure of GABA in order to better control the binding. This article explores the available synthetic methods, properties and activity of carbocyclic (cyclopropanes, cyclobutanes and cyclohexanes) and cage (adamantane and others) hydrocarbons - analogs of GABA with conformationally rigid carbon skeletons.

Computational and QSAR study of the alkylnaphthyl ketones adsorption on silver-ion stationary phase.

The chromatographic behaviour of alpha- and beta- alkylnaphthyl ketones at different temperatures on the silver-loaded stationary phase is described based on the QSRR model. Complexation via an oxygen atom is favoured over the interaction through the aromatic fragment. The QSRR model and DFT/MP2 studies suggest that retention times of alkylnaphthyl ketones on silver-containing stationary phases are determined primarily by the dipole moment, length of the alkyl substituent and concentration of modifier in the mobile phase.