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A series of fourteen new asymmetrical 1,3-diketone derivatives have been synthesized and evaluated in the ABTS, FRAP and DPPH assays as a new chemotype with antioxidant and drug-like properties. All the compounds displayed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y cell line. Among them, (3Z,5E)-6-(2,5-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (6b) and (3Z,5E)-6-(2,3-difluoro-4-hydroxy-phenyl)-1,1,1-trifluoro-4-hydroxyhexa-3,5-dien-2-one (7b) with excellent solubility and chemical stability in biorelevant media, have also shown a similar Fe+2 chelation behavior to that of curcumin. Additionally, both derivatives 6b and 7b have afforded good neuroprotection activity against H2O2 induced oxidative stress in the same neuronal cell line, with a significant reduction of intracellular ROS levels, in parallel with a good recovery of the Mitochondrial Membrane Potential (&Delta, &Psi, m). Compounds 6b and 7b with a promising antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitute a new interesting chemical class with high potential as new therapeutic agents against neurodegenerative diseases.

This work was financed by the Spanish Ministerio de Ciencia e Innovacion (MICINN) (CTQ2010-16122) and the Ministerio de Economia y Competitividad (MEC) (CTQ2012-35513-C02-02) and by the Comunidad Autonoma de Madrid (project MADRISOLAR2, ref. number S2009/PPQ-1533). The authors thank Dr. Ibon Alkorta for his help with the CSD and Dr. Ma Angeles Garcia for her assistance in recording the variable-temperature NMR spectra.

The structure of three fluorinated NH-indazolinones, two oxo derivatives and one 3-hydroxyindazole, has been determined by 13C and 15N solid state NMR. For two of them, X-ray crystallography confirmed the results on the tautomeric forms, 4,5,6,7-tetrafluoroindazolin-3-one crystallizing in P2 1/c monoclinic space group and 6,7-difluoroindazolin-3-one in P2 1/n monoclinic space group, proving once more the efficiency of the combined use of both techniques in structural determination. DFT theoretical calculations, gas phase, water-PCM and one explicit water molecule, support the results. © 2012 Elsevier B.V. All rights reserved.

3-Bromo-1-methyl-7-nitro-1H-indazole (1), 3-bromo-2-methyl-7-nitro-2H- indazole (2) and 3,7-dinitro-1(2)H-indazole (3) have been synthesized and characterized by X-ray diffraction, 13C and 15N NMR spectroscopy in solution and in solid-state. The dihedral angles obtained in the crystal structures are in good agreement with the molecular parameters calculated using DFT B3LYP calculations employing the 6-311++G(d,p) basis set. Compounds 1 and 2 present intermolecular halogen bonds between the bromine and the oxygen atoms of the nitro group and in compound 3 inter- and intramolecular hydrogen bonding exists. © 2010 Published by Elsevier B.V.

The enthalpies of combustion, heat capacities, enthalpies of sublimation and enthalpies of formation of 2-tert-butylbenzimidazole (2tBuBIM) and 2-phenylimidazole (2PhIM) are reported and the results compared with those of benzene derivatives and a series of azoles (imidazoles, pyrazoles, benzimidazoles and indazoles). Theoretical estimates of the enthalpies of formation were obtained through the use of atom equivalent schemes. The necessary energies were obtained in single-point calculations at the B3LYP/6-311++G(d,p) on B3LYP/6-31G* optimized geometries. The comparison of experimental and calculated values of all studied compounds bearing H (unsubstituted), methyl (Me) ethyl (Et), propyl (Pr), isopropyl (iPr), tert-butyl (tBu), benzyl (Bn) and phenyl (Ph) groups show remarkable homogeneity. The remarkable consistency of both the calculated and experimental results allows us to predict with reasonable certainty the missing experimental values. The crystal and molecular structure of the 2-benzylbenzimidazole (2BnBIM) has been determined by X-ray analysis. The observed molecular conformation permits the crystal being built up through N−H···N hydrogen bonds and van der Waals contacts between the molecules. An attempt has been made to relate the crystal structure to the enthalpies of sublimation., Thanks are due to Instituto de Cooperac¸a˜o Cientı´fica e Tecnolo´gica International (ICCTI), Lisbon, Portugal, and Consejo Superior de Investigaciones Cientı´ficas (CSIC), Madrid, Spain. L.M.P.F.A. thanks Fundac¸a˜o para a Cieˆncia e Tecnologia (FCT), Lisbon, Portugal, for the award of a postdoctoral fellowship (PRAXIS XXI/BPD/16319/98). This work has also been financed by DGICYT (BQU-2003- 00894, -00976 and -01251).

Six new 3(5)-trifluoromethyl-5(3)-substituted-styryl-1H-pyrazoles have been synthesized and their tautomerism studied in solution and in the solid state. The determination of their structures has been based on multinuclear NMR spectroscopy together with GIAO/B3LYP/6-311++G(d,p) theoretical calculations of eight structures for each pyrazole (two tautomers and four conformations). Five out of the six compounds present inhibition percentages of the iNOS isoform higher than 50%. With regard to the nNOS inhibitory activity, only two of the studied compounds show an inhibition of about 50%. Finally, concerning the eNOS, there is a compound presenting a low percentage of inhibition (40.2%) attaining in the other cases 50%., This work has been financed by Ministerio de Economía y Competitividad of Spain (CTQ2014-56833-R, RD12/0043/0005, and PI13-00981) and Comunidad Autonoma de Madrid (Project MADRISOLAR2, ref. S2009/PPQ-1533). One of us (C. I. Nieto) is indebted to UNED for a predoctoral fellowship (FPI “Grupos de Investigacion” UNED).

A series of new (E)-3(5)-[β-(aryl)-ethenyl]-5(3)-phenyl-1H-pyrazoles bearing fluorine atoms at different positions of the aryl group have been synthesized starting from the corresponding β-diketones. All compounds have been characterized by elemental analysis, DSC as well as NMR (H, C, F and N) spectroscopy in solution and in solid state. Three structures have been solved by X-ray diffraction analysis, confirming the tautomeric forms detected by solid state NMR. The in vitro study of their inhibitory potency and selectivity on the activity of nNOS and eNOS (calcium-calmodulin dependent) as well as iNOS (calcium-calmodulin independent) isoenzymes is presented. A qualitative structure-activity analysis allowed the establishment of a correlation between the presence/absence of different substituents with the inhibition data proving that fluorine groups enhance the biological activity. (E)-3(5)-[β-(3-Fluoro-4-hydroxyphenyl)-ethenyl]-5(3)-phenyl-1Hpyrazole (13), is the best inhibitor of iNOS, being also more selective towards the other two isoforms., This work has been financed by Ministerio de Ciencia e Innovación (CTQ2010-16122) and Ministerio de Economía y Competitividad of Spain (CTQ2014-56833-R, RD12/0043/0005, and PI13-00981) and Comunidad Autónoma de Madrid (Project MADRISOLAR2, ref. S2009/PPQ-1533). One of us (C. I. Nieto) is indebted to UNED for a predoctoral fellowship (FPI “Grupos de Investigación” UNED). We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).

The crystal and molecular structure of [14]paracyclo-bis-(1,2)pyrazoliumphane dibromide (1a) has been determined. The compound exists in the solid state in the chair (C) conformation while both chair (C) and boat (B) conformations are present in solution in comparable amounts. The barrier to the C ⇌ B interconversion has been determined by 1H NMR spectroscopy ( ΔG ‡ ≈ 17 kcal mol −1 ). AM1 semiempirical calculations conveniently reproduce the difference in stability between the chair (C) and the boat (B) conformations. [14]Paracyclo-bis-(1,2)pyrazolium-phane dibromide exists in the solid state in the chair conformation (X-ray crystallography) while both chair and boat conformations are present in solution in comparable amounts. The barrier to the chair boat interconversion has been determined by 1H NMR spectroscopy ( ΔG‡ ≈ 17 kcal mol −1 ).

The molecular and crystal structure of 2-(2′-hydroxyphenyl)imidazole (2) and 1-methyl-2-(2′-hydroxyphenyl)imidazole (5) have been determined by X-ray analysis. Compound (2) presents a strong intramolecular hydrogen bond (IMHB) responsible for the planarity of the molecule. In both compounds the molecules form chains through NH…O (compound 2) and OH…N hydrogen bonds (compound 5) but giving rise to the same packing mode. Ab initio calculations (6–31G∗∗) have been carried out on both compounds in order to study the effect of the IMHB on the structure.

The crystal and molecular structures of five 3(5)-amino-5(3)-arylpyrazoles differing in the nature of the substituent at the para position of the phenyl ring (1: X = H; 3.H2O: X = OCH3; 4: X = Cl; 5: X = Br and 6: X = NO2) have been determined by X-ray analysis. Three situations were detected in the crystal structures: the 3-tautomer is present in 1, 3 and 4; the 5-tautomer is only found in 6 and both tautomers (1:1) are observed in 5. The crystal packings are governed by NH… N O hydrogen bonds and also by OH…N interactions in the monohydrate of 3. It is worth noting that in 1, 3, 4 and 5 there are N-H…π(arene) contacts that might play a role in stabilizing the packing. Solid state 13C NMR results are consistent with the above crystallographic conclusions, thus allowing to determine that the only compound for which no good crystals have been obtained, the p-methyl derivative 2 should be a 3-amino tautomer. NMR solution studies (1H and 13C) allow to determine the 3-amino/5-amino tautomeric equilibrium constant, KT, which obeys a Hammett relationship with σp. Geometry optimizations of the 3 and 5-tautomers at semi-empirical level (AM1) were performed. In all compounds, the 3-tautomer has been found to possess a relatively lower energy by approximately 2 kcal mol−1. The potential energy surface as a function of the hybridization of the amino group and its conformation have also been analyzed.

Significant information on the structure of various bisazolium salts of the type CA2 (C++ 2A−) were revealed by the study of the FAB spectra of their positive and negative ions. Thus only one spectrum, whatever it consists of the positive or of the negative ions spectrum, enables the identification of the cation C++ and of the anion A−. Moreover, the same information are collected from the CAD spectrum of the adduct ion CA+ allowing the identification of such a compound in a mixture.

The structure and properties (crystallography, NMR, theoretical calculations) of the three N-unsubstituted benzazoles (1H-benzimidazoles, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles) have been reviewed for the period 2000-2012 with some results from previous years. The study of these compounds will greatly increase in the coming years and it is expected that the present review will contribute to it.

The carbon-13 chemical shifts and coupling constants of 1168 pyrazoles are reported, some of them in several solvents. These data are briefly discussed on the basis of statistical treatment and qualitative comparisons.

Reaction of NH-pyrazoles with 1-bromoadamantane in a high pressure stainless steel autoclave (250 ml, maximum working pressure of 200 atm) gives regioselectively 1-adamantyl or 4-adamantylpyrazoles depending on the temperature.

A computational study of the structural and thermochemical properties of N-phenyl (open) and N-alkyl (cyclic) ureas, through the use of M05-2X and B3LYP density functional theory calculations has been carried out. The consistency of the literature experimental results has been confirmed, and using mainly isodesmic reactions, the unknown ΔfH0(g) of the other urea derivatives were estimated. The experimental results together with the theoretical information have permitted the study of the effect of phenyl, p- and m-chlorophenyl, alkyl, and carbonyl substitutions on the thermodynamical stability of urea and its cyclic derivatives. The peculiar behavior of the N-tert-butyl substituent in cyclic ureas has been related to geometric deformations. © 2010 American Chemical Society.

The experimental gas-phase proton affinities (PAs) of 32 N-H and N-methyl pyrazoles have been determined by means of Fourier transform ion cyclotron resonance spectrosccopy (FTICR). Together with the previously reported PAs for 12 C-methyl-substituted pyrazoles, they provide a set of 57 data (counting each tautomer separately). The remarkably large spread of PAs, ca. 55 kcal.mol -1 , makes this set most suitable for structural analyses

Seven N-unsubstituted curcuminoid pyrazoles have been synthesized from the corresponding β-diketones (including curcumin). We evaluated the possibility of curcuminoid pyrazoles regulating the activity of matrix metalloproteinases (MMPs) by human intestinal epithelial cells in vitro. Zymographic analysis revealed that three compounds significantly down-regulated MMP-9 activity on inflammation-induced intestinal epithelial cells, making them original candidates for the treatment of inflammatory bowel disease (IBD). © 2008 Elsevier Ltd. All rights reserved.

The 13 C chemical shifts and the 1 J ( 1 H- 13 C) coupling constants of the title compounds are relatively sensitive to solvent effects (Δδ = 2–3 ppm, Δ J = 2–3 Hz), deuterochloroform values being near the averaged ones (11 solvents). The solvent induced shifts of the three heterocyclic carbons and those of the N -methyl groups are discussed using the Kamiet—Taft—Abboud formalism. As solvent (pure liquid) 1-methylimidazole appears as a highly dipolar-polarizable solvent

The intrinsic basicity of 24 azoles (pyrazoles, indazoles, imidazoles, benzimidazoles) and 7-methylazaindole was determined by mass spectrometry techniques, ion cyclotron resonance (ICR) and/ or chemical ionization (CI) in conjunction with tandem mass spectrometry (MS/MS). A reasonably good agreement (r 2 =0.967) is found between both methods (15 compounds). Thus, it is possible to use CI/MS/MS to determine the intrinsic basicity of compounds not measurable by ICR for purity or volatility reasons. Some anomalies are interpreted in terms of entropy and steric effects. The basicity data are also discussed by using empirical models (σα, σ R ) and chelation and annelation effects

An extraordinary inversion of the regioselectivity in the reaction of C-adamantylation of pyrazoles by 1-bromoadamantane was observed when the autoclave vessel was replaced by a microwave oven. In these last conditions mono and disubstituted 3(5)-(1-adamantyl) pyrazoles were obtained.

Reaction of NH-pyrazoles with 1-bromoadamantane in a high pressure stainless steel autoclave (250 ml, maximum working pressure of 200 atm) gives regioselectively 1-adamantyl or 4-adamantylpyrazoles depending on the temperature.

Reaction of NH-pyrazoles with 1 -bromoadamantane in a high pressure stainless steel autoclave gives regioselectively 1-(1 -adamantyl)or 4-(1-adamantyl)pyrazoles depending on the temperature. A series of cross-experiments allows to establish the mechanism of this reaction. The molecular structure of the most simple derivative, 4-(1-adamantyl) pyrazole (3a), has been determined. Intermolecular N−H...N hydrogen bonds hold the four independent molecules together in a helix system parallel to the c axis. The crystal is built up of two centrosymmetrically related helices

Crystal structures of 1-(1-adamantyl)pyrazole, 1a, and 1-(1-adamantyl-3-ol)-4-nitropyrazole, 2a, have been solved by X-ray analysis. The space groups and cell parameters are P21, a, 7.4021(3), b, 10.7529(5),c, 6.9651(2)A, β, 90.206(3)° for 1a with Z = 2 and P2/n, a, 31.1172(14), b, 6.8506(1), c, 12.0313(3)A, β 94.873(3)° for 2a with Z = 8. Refinements were carried out down to R values of 0.043 (Rw, = 0.046) and 0.079 (Rw = 0.061) for the 951 (2σ(I)) and 2461 (3σ(I)) observed reflections respectively. The conformation about the bond between the heterocycle and the carbocycle is discussed on theoretical grounds INDO calculations): the adamantane behaves as a free rotor. The stcricinteractions of the adamantyl residue with the methyl substituents in 2- and 5-position of pyrazole are apparent in the C-13 chemical shifts.

The crystal structures of 1-(1-adamantyl)-3,5-dimethylpyrazole 1 and 1-(1-adamantyl)-3,4,5-trimethylpyrazole 2 were studied by X-ray analysis. The space groups and cell parameters are: 1, Cc, 13.4452(4), 14.9407(4), 7.1119(2) A, 90, 111.944(2), 90°, with Z = 4. 2, P21/c, 6.7466(1), 21.2565(7), 10.1462(2) A, 90, 106.368(2), 90°, with Z = 4. The final disagreement factors were 0.069 and 0.061, for 721 [2σ(I)] and 1950 [2σ(I)] observed reflexions, respectively. Compound 1 presents the adamantyl residue disordered between the two usual conformations. The experimental dipole moments and the carbon-13 chemical shifts (both in hexadeuteriodi-methylsulfoxide and in the solid state) were measured and discussed in connection with the structure of these compounds.

Using a series of equations connecting experimental and theoretical values, it is possible to discuss the origin of the N-methylation effect in azoles dissolved in water and dimethyl sulphoxide. The existence in the azoles studied of a linear relationship between the gas → solution transfer enthalpies and the charge on the pyrrole hydrogen atom demonstrated the fundamental importance of the loss of an active centre for solvation. For the imidazole–N-methylimidazole pair, the complete thermochemical cycle has been determined, allowing the apparent lack of an effect of N-methylation on the basicity in solution to be discussed.

Twenty symmetrical and asymmetrical 1,2-bisazolylethanes have been obtained from azoles and 1,2-dibromoethane or 1-chloro-2-(pyrazol-1-yl)ethane by phase transfer catalysis (PTC). The 1H and 13C nmr properties are reported and the chemical shifts of the ethylene carbon atoms discussed using an additive model.

Using 1-adamantylhydrazine as starting material, a series of 1-(1-adamantyl)pyrazoles has been prepared. Electrophilic reactivity (bromination and nitration) and nucleophilic reactivity (quaternarization) have been studied. Proton nuclear magnetic resonance spectra of all the new compounds are recorded.

The crystal and molecular structure of the title compound (Me2-TPzT) has been determined by X-ray analysis. The observed molecular conformation presents the nitrogen atoms of three pyrazole rings in the same relative positions. The molecules are joined through intermolecular contacts forming chains that are arranged in a distorted hexagonal symmetry. Two complexes containing this ligand have been prepared: [{Pd(en)}3(Me2-TPzT)](PF6)6 and [{Ag(PPh3)}3(Me2-TPzT)](ClO4)3, which, due to their insolubility, have been characterized only by microanalysis, IR, 1H NMR and, in the latter case, by mass spectrometry.