RESUMO
The search of new antioxidants, as drugs candidates, is an active field of medicinal chemistry. The synthesis of compounds with antioxidant potential has increased in recent years and a high number of structurally diverse compounds have been published. This review aims to show the current state-of-the-art on the development of antioxidant compounds incorporating the pyrazole pharmacophore. It is a well-timed review driven by the increasing number of papers, on this issue, that have been published since the beginning of the 21st century (from 2000 to 2017). The aim is to look deeper into the structures already published in the literature containing the pyrazole core as the unique pharmacophore or combined with other pharmacophores and see the relationship between the presence of this five-membered nitrogen heterocycle and the behaviour of the compounds as potential antioxidant agents. An attempt was made to whenever possible establish structure-activity relationships that could help the design of new and more potent antioxidant agents containing this important pharmacophore.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Animais , Descoberta de Drogas/métodos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.
Assuntos
Oxazóis/síntese química , Oxazóis/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Depressores do Apetite/síntese química , Depressores do Apetite/farmacologia , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ligantes , Modelos Moleculares , Conformação Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
1H-indazoles are good candidates for studying the phenomena of molecular association and spontaneous resolution of chiral compounds. Thus, because the 1H-indazoles can crystallize as dimers, trimers, or catemers, depending on their structure and the phase that they are in, the difficulty in the experimental analysis of the structure of the family of 1H-indazoles becomes clear. This difficulty leads us to contemplate several questions: How can we determine the presence of different structures of a given molecular species if they change according to the phase? Could these different structures be present in the same phase simultaneously? How can they be determined? To shed light on these questions, we outline a very complete strategy by using various vibrational spectroscopic techniques that are sensitive (VCD) and insensitive (IR, FIR, and Raman) towards the chirality, together with quantum chemical calculations.
RESUMO
Seven N-unsubstituted curcuminoid pyrazoles have been synthesized from the corresponding beta-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).
Assuntos
Curcumina/farmacologia , Doenças Inflamatórias Intestinais/enzimologia , Inibidores de Metaloproteinases de Matriz , Pirazóis/farmacologia , Células CACO-2 , Curcumina/síntese química , Curcumina/química , Gelatinases/metabolismo , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-1beta/metabolismo , Pirazóis/síntese química , Pirazóis/química , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The (1)H and (13)C NMR spectra of two stereoisomeric bis-Tröger's bases and four stereoisomeric tris-Tröger's bases asymmetrically substituted on the external aromatic rings were recorded and the corresponding signals assigned. The relative configuration of the stereogenic units has been unequivocally determined on the basis of homoallylic couplings and NOE experiments.
Assuntos
Azocinas/química , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Isótopos de Carbono , Conformação Molecular , Prótons , Valores de Referência , EstereoisomerismoRESUMO
Using high-resolution solid-state (15)N CMAS NMR, X-ray crystallography, and ab initio calculations, we have studied the structure of solid pyrazole-4-carboxylic acid (1). The crystal structure was determined at 295 and 150 K. Molecules of 1 are located on a two-fold axis, implying proton disorder of the NH and OH groups; no phase transition was observed between these two temperatures. The compound forms quasi-linear ribbons in which the molecules are linked by cyclic hydrogen bonds between pyrazole and carboxylic acid groups with disordered hydrogen-bonded protons. Crystallography is unable to decide whether the disorder is dynamic or static. NMR shows that this disorder is dynamic, that is, consisting of very fast degenerate double proton transfers between two rapidly interconverting O-H.N and O.H-N hydrogen bridges. However, at low temperature, NMR shows a proton disorder-order transition where the protons are preferentially localized on given nitrogen and oxygen atoms. An amorphous phase exhibiting proton order is observed when the compound is precipitated rapidly. In this case, the defects are annealed by moderate heating. Ab initio calculations performed on oligomers of 1 show that the O-H.N hydrogen bridge is about 0.064 A shorter and less bent ( approximately 171 degrees ) than the O.H-N hydrogen bridge ( approximately 150 degrees ). For an isolated ribbon, this result leads to structures with localized protons, either to a cycle with about 200 molecules, or to a quasi-linear ribbon involving an undulated structure, or to a combination of both motifs. Only the undulated structure is compatible with the linear ribbon observed by X-ray crystallography, where the fast proton transfer in the high-temperature phase is assisted by the motions of the undulated chain. A disordered structure is assigned to the amorphous phase, which exhibits the combination of the curved and the undulated motifs.
RESUMO
The gas-phase basicity (GB) of tetra-tert-butyltetrahedrane (tBu4THD) was determined by FT-ICR mass spectrometry and comparison with reference compounds of known basicity. Its GB, 1035+/-10 kJ x mol(-1), makes tetra-tert-butyltetrahedrane one of the strongest bases reported so far. Ab initio calculations [B3LYP/6-31G(d) and B3LYP/6-311 + G(d,p)//6-31G(d)] have been carried out in order to compare the high experimental basicity of tBu4THD with that estimated theoretically. Both B3LYP/6-31G(d) and QCISD(T) calculations were used to determine the reaction path which connects the initial tetrahedrane-ammonium complex with the final products, protonated cyclobutadiene (CBDH+) and ammonia.
RESUMO
A convenient synthesis of 5alpha,8alpha,14alpha,17alpha-5,17:8,14-dimethano-5,8,14,17-tetraaza-5,6,7,8,13,14,17,18-octahydrodibenzo[e,e']benzo[1,2-a:3,4-a']dicyclooctene derivatives is described, and the compounds have been fully characterized by NMR; in some cases, the molecular structure has been determined by X-ray crystallography. These compounds represent the first examples of a new class of molecular tweezers.
RESUMO
Proton transfer between dimers is associated with strong bases and very good hydrogen bond donors, namely, between very different chemical species. A spontaneous self-ionization and concomitant proton transfer can occur in dimers involving phosphinic acid derivatives (see picture), even when they present the same functional group. It is also possible, by choosing the appropriate substituents, to modulate the degree of the interaction, from a hydrogen bonded complex to an ion pair, without changing the nature of the functional groups involved.
RESUMO
The secondary structure of 1H-unsubstituted pyrazole derivatives bearing only one hydrogen donor group and one or more acceptor groups has been analyzed in terms of some descriptors representing the substituents at C3 and C5. The substituent at C4 appears to affect mainly the tertiary or quaternary structure of these compounds. The proposed semi-quantitative model, which explains most hydrogen-bonded motifs as a combination of the effects of substituents at C3 and C5, has also been examined as a function of the steric and polarizability effects of these substituents represented by molar refractivity. The model also applies to other five-membered rings (1,2,4-triazoles, 1,2,4-diazaphospholes and 1,2, 4-diazaarsoles). Furthermore, ab initio calculations at RHF/6-31G* have been performed to discover the relative stability of three of the four hydrogen-bond patterns displayed by several symmetrical pyrazoles (dimers, trimers, tetramers). The fourth motif, catemers, has only been discussed geometrically.
Assuntos
Pirazóis/química , Cristalografia por Raios X , Dimerização , Hidrogênio , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The infrared (IR) and Raman spectra of 3,5-dimethylpyrazole have been recorded in the vapor, liquid (melt and solution) and solid states. Two deuterated derivatives, C5H7N-ND and C5D7N-NH, were also studied in solid state and in solutions. Instrumental resolution was relatively low, 2.0 cm(-1) in the IR and approximately 2.7 cm(-1) in the Raman spectra. The solids are made of cyclic hydrogen-bonded trimers. These trimers, present also in chloroform and acetone solutions, give rise to characteristic high absorption IR spectra in the 3200-2500 cm(-1) region, related to Fermi resonance involving nu(NH) vibrations. Bands from trimers are not present in water solutions but these solutions show spectral features similar in several ways to those of the trimer, attributable to solvent-bonded complexes. Evidence of H-bonding interactions with the other solvents is also visible in the high-frequency region. The two very intense bands in the Raman spectra of the solids appearing at 115 and 82 cm(-1) in the parent compound are also connected with a trimer formation. To interpret the experimental data, ab initio computations of the harmonic vibrational frequencies and IR and Raman intensities were carried out using the Gaussian 94 program package after full optimization at the RHF/6-31G* level for the three monomeric compounds as well as for three models of the trimer, with C3h, C3 and C1 symmetry. The combined use of experiments and computations allow a firm assignment of most of the observed bands for all the systems. In general, the agreement between theory and experiment is very good, with the exception of the IR and Raman intensities of some transitions. Particularly noticeable is the failure of the theoretical calculation in accounting for the high intensity of the Raman bands of the solid about 115 and 82 cm(-1).
Assuntos
Pirazóis/química , Deutério , Estrutura Molecular , Espectrofotometria Infravermelho/métodos , Análise Espectral Raman/métodosRESUMO
The ligands 4,6-bis(pyrazol-1-yl)pyrimidine (bpzpm) and 4,6-bis(4-methylpyrazol-1-yl)pyrimidine (Me-bpzpm) were synthesized and their reactions with some palladium derivatives explored. Mononuclear or dinuclear neutral or cationic complexes were obtained by reaction of the ligands with 1 or 2 equiv of Pd(C6XF4)2(cod) (cod = 1,5-cyclooctadiene; X = F, H) or the palladium fragment [Pd(eta 3-2-Me-C3H4)(S)2]+ (S = acetone). The reaction of the dinuclear derivatives with 1 equiv of the respective free ligand immediately led to the regeneration of the mononuclear complexes. Except in the case of the synthesis of [[Pd(C6HF4)2][Pd(C6F5)2](bpzpm)], where two similar metallic groups are present, all attempts to obtain dinuclear asymmetric complexes with two different palladium fragments failed. Instead, the dinuclear symmetric complexes were formed. This result could be considered as an example of molecular recognition with the ligand acting as a ditopic receptor. This behavior is comparable to chemical symbiosis but in this case applied to the ligand rather than to the metal center as occurs normally. The polyfluorophenyl rings are situated on average in a perpendicular orientation with respect to the coordination plane. Their restricted rotation results in several atropoisomers for the complexes with m-C6HF4. Different cross-reaction experiments were carried out, and these showed the mobility of the metallic fragments, with the more difficult process being that involving the more strongly bonded polyfluorophenyl palladium groups. By means of 1H NMR variable temperature studies, the interconversion of the two isomers of [[Pd(eta 3-C4H7)]2-(bpzpm)]Tf2 (Tf = CF3SO3) was analyzed. In the case of [[Pd(eta 3-C4H7)](bpzpm)]Tf the existence of two processes, an intramolecular apparent allyl rotation and an intermolecular exchange of the allylpalladium fragments, has been demonstrated. Different delta Gc++ values at the coalescence temperatures have also been determined. An X-ray single-crystal analysis was carried out on [[Pd(eta 3-C4H7)]2(bpzpm)]Tf2, which crystallizes in the monoclinic system, space group I2/m, with a = 9.368(2), b = 16.191(3), c = 20.228(6) A, beta = 101.26(3), and Z = 4. Compound [[Pd(C6HF4)2](bpzpm)] crystallized in the triclinic system, space group P1, with a = 8.845(6), b = 12.6609(9), c = 12.826(3) A, alpha = 88.45(2), beta = 74.36(3), gamma = 89.32(2), and Z = 2.
RESUMO
The crystal and molecular structures of 3(5),4-dimethylpyrazole, C(5)H(8)N(2), (I), and of 3,4,5-trimethylpyrazole, C(6)H(10)N(2), (II), have been determined at 200 K. In (I) the 4,5-dimethylpyrazole tautomer is present in the solid state and the six independent molecules in the asymmetric unit form trimers via NH.N hydrogen bonds related by a pseudo centre of symmetry. The asymmetric unit of (II) contains one and a half molecules: these exhibit NH proton disorder and are hydrogen bonded to each other via their respective NH groups to form chains. Ab initio calculations at HF and B3LYP/6-31G** levels indicate that the 3,4-dimethylpyrazole tautomer is more stable than the 4,5-dimethylpyrazole tautomer by only approximately 0.5 kcal mol(-1) (1 kcal mol(-1) = 4.184 kJ mol(-1)).
RESUMO
A series of eighteen substituted pyrazoles, bis- and tris-azolyl-methanes or ethanes was investigated for their interaction with the zinc enzyme carbonic anhydrase (CA). Several types of activities were detected, generally as CA activators, but Ca inhibitory properties were also discovered for the very sterically-demanding derivatives of these series. Kinetic determinations by a stopped-flow technique for carbon dioxide hydration reaction allowed the determination of Michaelis-Menten constants, which are identical in the absence or in the presence of these modulators, proving a noncompetitive mechanism of activation-inhibition. MNDO calculations were used with moderate success to explain the biological results.
Assuntos
Anidrases Carbônicas/efeitos dos fármacos , Isoenzimas/efeitos dos fármacos , Metano/farmacologia , Pirazóis/farmacologia , Animais , Bovinos , Ativação Enzimática , CinéticaRESUMO
New derivatives of diphenylsulfone have been synthesized and their antibacterial and antifungal activities evaluated. Their chemical structures have been established by means of analytical and NMR spectroscopic data.
Assuntos
Anti-Infecciosos/síntese química , Sulfonas/síntese química , Antibacterianos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Sulfonas/química , Sulfonas/farmacologiaRESUMO
A correlation was found between the carbonic anhydrase II activating power and the pKa values for a series of azoles, bisazolylmethanes and bisazolylethanes. Strong activations were found for compounds with pKa's in the interval 6.5-8.0. The mechanism of action for such activators is discussed.
Assuntos
Azóis/farmacologia , Anidrases Carbônicas/metabolismo , Isoenzimas/metabolismo , Ativação Enzimática , CinéticaRESUMO
The pi (hydrophobic constant) values for 16 parent azoles (pyrrole, imidazole, pyrazole, four triazoles, two tetrazoles, indole, benzimidazole, 1H- and 2H-indazoles, 1H- and 2H-benzotriazoles, and carbazole) were calculated from the logarithms of the capacity factors (log k') determined by HPLC. The values thus obtained are discussed according to an additive model in which the number and position of pyridinelike nitrogen atoms and the annelation effect are considered.