The geometric stereoisomers of 3-carbomethoxy-3-methyl-4-bromo-1-pyrazoline have been prepared. Both compounds have been found to be highly unstable and are transformed readily into the hydrobromide salt of 3-methyl-4-carbomethoxypyrazole. This transformation requires preferential migration of a carbomethoxy group over a methyl group. A stepwise mechanism is proposed for this rearranagement. Pyrolysis of 3-carbomethoxy-3-cyano-4-methyl-4-aryl-1-pyrazoline, (Z)-and (E)- gives predominantly the olefin expected for concerted migration with elimination of nitrogen. The transition state is described by a structure in which there is no bond breaking of C(5)-N bond. This mechanism is supported by (i) the lack of a C(5) secondary ⍺-deuterium kinetic isotope effect, (ii) the negative value of the entropy of activation, and (iii) the migratory aptitudes between various substituted aryl groups. The possibility of a short-lived intermediate is not completely ruled out. However, the lack of a large effect of solvent polarity on the rate of reaction and the stereospecificity of the reaction suggest the intermediate of the pyrazoline pyrolysis cannot be a zwitterion with free rotation about the C(3)-C(4) bond. / Science, Faculty of / Chemistry, Department of / Graduate

O presente trabalho consiste na síntese, caracterização e estudos de atividade tripanocida de doze compostos, sendo oito tiossemicarbazonas (TSCs) e quatro ditiocarbazatos (DTCs), contendo anel pirazolínico em suas estruturas, assim como no estudo da formação de complexos de um DTC com GaIII. As TSCs e os DTCs foram obtidos em reações de condensação envolvendo uma β-dicetona e uma tiossemicarbazida ou ditiocarbazato, respectivamente. A partir de 1-fenil-1,3-butanodiona (benzoilacetona) e 4-R-tiossemicarbazida, foram obtidas as TSCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2bt, H2bmt, H2bet e H2bpt, com R = H, Me, Et e Ph, respectivamente. Mudando a β-dicetona para 4,4,4-trifluoro-1-fenil-1,3-butanodiona, foram obtidas as TSCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2ft, H2fmt, H2fet e H2fpt, com R = H, Me, Et e Ph, respectivamente. De modo similar, os DTCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2bdtc e H2mbdtc, para R = H e OMe, respectivamente, foram obtidos a partir de benzoilacetona e S-p-R-benzilditiocarbazato, enquanto que os DTCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2fdtc e H2mfdtc, para R = H e OMe, respectivamente, formaram-se quando a 4,4,4-trifluoro-1-fenil-1,3-butanodiona foi a β-dicetona utilizada. Os compostos foram caracterizados por diversas técnicas, que incluíram análise elementar, espectroscopia na região do infravermelho (IV), espectrometria de massas, ressonância magnética nuclear de hidrogênio e flúor (RMN1H e 19F) e difração de raios X em monocristal. As TSCs e os DTCs foram avaliados quanto a suas atividades anti-T. cruzi e citotoxicidade frente a células de macrófagos J774, sendo possível avaliar as influências dos grupos periféricos substituintes. Nestes estudos, dois novos compostos, além do H2bdtc, cuja atividade é conhecida, se mostraram promissores, H2bt e H2bmt, apresentando valores de atividade tripanocida CC50try = 9,91 e 6,85 µM, respectivamente, para a cepa Y na forma tripomastigota do T. cruzi. Ambos foram superiores ao benzonidazol, utilizado como referência (CC50try = 10,6 µM). Os compostos também se mostraram seletivos, com CC50 > 100 µM para células de macrófago J774. Estudos de complexação com GaIII utilizando H2bdtc como agente complexante levaram a dois novos complexos, variando-se as condições reacionais, sendo um mononuclear, [Ga(bdtc)(Hbdtc)].CH3OH, e um dinuclear, [Ga2(bdtc)2(µOCH3)2].CH2Cl2, os quais foram caracterizados, tanto em solução quanto no estado sólido, tendo tido suas estruturas determinadas por difração de raios X em monocristal. Ambos apresentam centros de GaIII pentacoordenados, com grau de distorção diferenciado, entre uma geometria de coordenação bipiramidal trigonal e piramidal de base quadrada. Quando dianiônico, o bdtc2- coordenou-se O,N,S-tridentado, diferentemente da forma S,N-bidentada observa para o DTC, quando coordenado monoaniônico, como bdtc1-. / The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a & beta;-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the & beta;-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(µ OCH3)2].CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a ?-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the ?-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(?-OCH3)2]·CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.

O presente trabalho consiste na síntese, caracterização e estudos de atividade tripanocida de doze compostos, sendo oito tiossemicarbazonas (TSCs) e quatro ditiocarbazatos (DTCs), contendo anel pirazolínico em suas estruturas, assim como no estudo da formação de complexos de um DTC com GaIII. As TSCs e os DTCs foram obtidos em reações de condensação envolvendo uma β-dicetona e uma tiossemicarbazida ou ditiocarbazato, respectivamente. A partir de 1-fenil-1,3-butanodiona (benzoilacetona) e 4-R-tiossemicarbazida, foram obtidas as TSCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2bt, H2bmt, H2bet e H2bpt, com R = H, Me, Et e Ph, respectivamente. Mudando a β-dicetona para 4,4,4-trifluoro-1-fenil-1,3-butanodiona, foram obtidas as TSCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(4-R-tiossemicarbazona), identificados como H2ft, H2fmt, H2fet e H2fpt, com R = H, Me, Et e Ph, respectivamente. De modo similar, os DTCs de nome 5-hidroxi-3-metil-5-fenil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2bdtc e H2mbdtc, para R = H e OMe, respectivamente, foram obtidos a partir de benzoilacetona e S-p-R-benzilditiocarbazato, enquanto que os DTCs de nome 5-hidroxi-3-fenil-5-trifluorometil-pirazolina-1-(S-p-R-benzilditiocarbazato), H2fdtc e H2mfdtc, para R = H e OMe, respectivamente, formaram-se quando a 4,4,4-trifluoro-1-fenil-1,3-butanodiona foi a β-dicetona utilizada. Os compostos foram caracterizados por diversas técnicas, que incluíram análise elementar, espectroscopia na região do infravermelho (IV), espectrometria de massas, ressonância magnética nuclear de hidrogênio e flúor (RMN1H e 19F) e difração de raios X em monocristal. As TSCs e os DTCs foram avaliados quanto a suas atividades anti-T. cruzi e citotoxicidade frente a células de macrófagos J774, sendo possível avaliar as influências dos grupos periféricos substituintes. Nestes estudos, dois novos compostos, além do H2bdtc, cuja atividade é conhecida, se mostraram promissores, H2bt e H2bmt, apresentando valores de atividade tripanocida CC50try = 9,91 e 6,85 µM, respectivamente, para a cepa Y na forma tripomastigota do T. cruzi. Ambos foram superiores ao benzonidazol, utilizado como referência (CC50try = 10,6 µM). Os compostos também se mostraram seletivos, com CC50 > 100 µM para células de macrófago J774. Estudos de complexação com GaIII utilizando H2bdtc como agente complexante levaram a dois novos complexos, variando-se as condições reacionais, sendo um mononuclear, [Ga(bdtc)(Hbdtc)].CH3OH, e um dinuclear, [Ga2(bdtc)2(µOCH3)2].CH2Cl2, os quais foram caracterizados, tanto em solução quanto no estado sólido, tendo tido suas estruturas determinadas por difração de raios X em monocristal. Ambos apresentam centros de GaIII pentacoordenados, com grau de distorção diferenciado, entre uma geometria de coordenação bipiramidal trigonal e piramidal de base quadrada. Quando dianiônico, o bdtc2- coordenou-se O,N,S-tridentado, diferentemente da forma S,N-bidentada observa para o DTC, quando coordenado monoaniônico, como bdtc1-. / The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a & beta;-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the & beta;-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(µ OCH3)2].CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.The present work describes the synthesis, structural characterization and trypanocidal activity studies of twelve compounds, eight thiosemicarbazones (TSCs) and four dithiocarbazates (DTCs) containing pyrazoline ring in their structures, as well as in the study of complex formation of a DTC with GaIII. The TSCs and DTCs were obtained from condensation reactions involving a ?-diketone and a dithiocarbazate or thiosemicarbazide, respectively. From 1-phenyl-1,3-butanedione (benzoylacetone) and 4-R-thiosemicarbazide were obtained TSCs the name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2bt, H2bmt, H2bet and H2bpt, R = H, Me, Et, Ph, respectively. Changing the ?-diketone for 4,4,4-trifluoro-1-phenyl-1,3-butanedione result in TSCs the name 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(4-R-thiosemicarbazone), identified as H2ft, H2fmt, H2fet and H2fpt, R = H, Me, Et, Ph, respectively. Similarly, the DTCs with name 5-hydroxy-3-methyl-5-phenyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2bdtc and H2mbdtc to R = H and OMe, respectively, were obtained from benzoylacetone and S-p-R-benzyldithiocarbazate, while DTCs 5-hydroxy-3-phenyl-5-trifluoromethyl-pyrazoline-1-(S-p-R-benzyldithiocarbazate), H2fdtc and H2mfdtc to R = H and OMe, respectively, are formed with 4,4,4-trifluoro-1-phenyl-1,3-butanedione. The compounds were characterized by various techniques such as elemental analysis, infrared spectroscopy (IR), mass spectrometry, nuclear magnetic resonance of hydrogen and fluorine (1H and 19F NMR) and single crystals X-ray diffraction. The TSCs and DTCs were evaluated for their anti-T. cruzi activity and cytotoxicity against macrophage cells, making it possible to evaluate the effects of substituent peripheral groups. In these studies, other two new compounds than H2bdtc whose activity is known, were considered promising, H2bt and H2bmt, having superior activity, CC50try values 9.91 and 6.85 µM, respectively, compared with benznidazole used as reference (CC50try = 10.6 µM). The compounds also show selective with CC50> 100 µM for J774 macrophage cells. In the complexation studies with GaIII using H2bdtc it is possible to obtain two new complex, varying the reaction conditions, being a mononuclear, [Ga(bdtc)(Hbdtc)]·CH3OH, and other dinuclear [Ga2(bdtc)2(?-OCH3)2]·CH2Cl2, which were characterized both in solution and in solid state, having their structures determined by single crystals X-ray diffraction. Both having GaIII pentacoordenate, with distortion of coordination geometry between trigonal bipyramidal and square pyramidal. When the ligand bdtc2- coordinated dianionic the form is O,N,S-tridentate, unlike the form S,N-bidentate was observed for the DTC when coordinated monoanionic as bdtc1-.

The main theme of this thesis is to develop a fluorescent probe for imaging the subcellular distribution of kinetically labile copper pools that might play a critical role in copper homeostasis. Various copper-selective sensors were designed by combining 1,3,5-triaryl-2-pyrazoline fluorophores with polythioethers as receptor moieties. A series of donor-substituted 1,3,5-triaryl-2-pyrazoline fluorophores were synthesized and characterized in terms of their photophysical and electrochemical properties. Interestingly, the aryl substituents attached to the 1- and 3-position of the pyrazoline ring influence the photophysical properties of the fluorophore in distinctly different ways. The excited-state equilibrium energy is primarily influenced by changes of the substituent in the 1-position, whereas the reduction potential of the fluorophore is determined by the 3-aryl group. Results from computational analyses agree well with the experimental data. A pyrazoline fluorophore library was synthesized, and their photophysical and electrochemical properties were studied. The compounds cover a broad range of excited state energies and reduction potentials, and allow for selective and differential tuning of these two parameters. A series of thiazacrownethers and tripodal aniline copper(I) receptors were synthesized and their copper binding stoichiometries, stability constants, and copper-self-exchange kinetics were investigated. The measured self-exchange activation parameters revealed for all studied ligands a negative activation entropy, suggesting a predominant associative exchange mechanism. With detailed knowledge of the fluorophore platform and copper receptors, sensor CTAP-1 was designed, synthesized and characterized. The probe shows a 4.6-fold emission enhancement and reaches a quantum yield of 14% upon saturation with Cu(I). The sensor exhibits excellent selectivity towards Cu(I) and is insensitive towards millimolar concentrations of Mg(II) or Ca(II). Mouse fibroblast cells (3T3) incubated with the sensor produced a copper-dependent perinuclear staining pattern, which colocalizes with the subcellular location of the mitochondria and the Golgi apparatus. The subcellular topography of copper was further determined by synchrotron-based x-ray fluorescence (SXRF) microscopy. Furthermore, microprobe x-ray absorption measurements at various subcellular locations showed a near-edge feature that is characteristic for low-coordinate monovalent copper. The data provide a coherent picture with evidence for a kinetically labile copper pool, which is predominantly localized in the mitochondria and the Golgi apparatus.

Fluorescence microscopy is a powerful analytical tool for visualizing biological processes at the subcellular level. In this regard, 1,3,5-triarylpyrazoline based fluorescent probes which act as "turn-on" probes, have been extensively researched. These probes achieve their fluorescence "turn-on" response by inhibition of fluorescence quenching by acceptor-excited photoinduced electron transfer upon binding of an analyte. It has been recently shown that some fluorescent probes used in biological research form colloids composed of nanoparticles, due to their hydrophobic character. This hydrophobic character can also lead to partitioning of the probe into cellular membranes. Colloid formation and membrane partitioning may affect the probes' photophysical properties such as absorption and emission wavelength and quantum yields. Recently, a series of 1,3,5-triarylpyrazolines synthesized in our group by M. T. Morgan, showed no formation of aggregates in aqueous buffer. Surprisingly, these probes increased their fluorescence intensity in the presence of liposomes. The photoinduced electron transfer process is greatly affected by the polarity of the medium in which the probe is used. In this study, the effect of membrane proximity on the photoinduced electron transfer process for pyrazoline based "turn-on" probes has been investigated. A series of water soluble 1,3,5-triarylpyrazolines have been synthesized in which a N,N-dialkylaniline moiety acts as an electron donor and a proton acceptor and an alkylated sulfonamide moiety acts as a molecular anchor for interaction with neutral and anionic liposomes.

Pain is a common symptom in clinical practice and many advances have been observed in order to obtain more effective analgesic molecules with fewer side effects. The present study evaluated the antinociceptive potential of four novel pyrazoles: 3-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF3), 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4), 3-methyl-5-trichloromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPCl3), and 4-methyl-5-trichloromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPCl4). The systemic administration of the compounds was effective for the inhibition of the nociception in chemical (formalin test, 0.03 -1.0 mmol/kg, i.p.) and thermal (hot-plate test, 0.1-1.0 mmol/kg, i.p.) models of pain. In addition, MPF4 also produced antinociception in models of inflammatory pain induced by Complete Freund s Adjuvant (CFA) or by incision procedure in paw of mice. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was not reversed by yohimbine (0.15 mg/kg, i.p.) or p-chlorophenylalanine ethyl ester (PCPA; 300 mg/kg, i.p.), but by naloxone (2.0 mg/kg, i.p.), in both thermal and chemical nociception. Animals given MPF4 (1.0 mmol/kg, i.p.) daily for 8 days in a row, in contrast to morphine (5 mg/kg, i.p.), showed no tolerance to its antinociceptive effect or cross-tolerance with morphine. However, similarly to morphine (11 mg/kg, i.p.), MPF4 (1.0 mmol/kg, i.p.) reduced gastrointestinal transit in mice and its effect was reversed by naloxone (2.5 mg/kg, i.p.). Unlike indomethacin (0.1 mmol/kg, p.o.), MPF4 (1.0 mmol/kg, p.o.) did not induce gastric lesions in mice. The tested compounds did not impair locomotion in the mice as well. Taken together, the results demonstrate that these novel pyrazoline methyl esters evaluated may be promising prototypes of additional mild analgesics, which are therapeutically relevant. / A dor é um sintoma comum na prática clínica, por isso muitos avanços estão sendo realizados no sentido de obter moléculas analgésicas cada vez mais efetivas e com menos efeitos colaterais. Neste contexto, no presente estudo avaliou-se o potencial antinociceptivo de quatro pirazóis inéditos: 3- metil-5-hidroxi-5-trifluormetil-4,5-diidro- 1H-pirazol metil éster (MPF3), 4-metil-5-hidroxi-5-trifluormetil-4,5-diidro-1H-pirazol metil éster (MPF4), 3-metil-5-hidroxi-5-triclorometil-4,5-diidro-1H-pirazol metil éster (MPCl3) e 4-metil-5-hidroxi-5-triclorometil-4,5-diidro-1H-pirazol metil éster (MPCl4). A administração sistêmica dos compostos foi efetiva em inibir a nocicepção em modelos de dor induzida por estímulo nocivo químico (teste da formalina, 0,03-1,0 mmol/kg, i.p.) e térmico (teste da placa-quente, 0,1-1,0 mmol/kg, i.p.). Em adição, MPF4 produziu antinocicepção em modelos de dor inflamatória causada por Adjuvante Completo de Freund (ACF) ou por incisão na pata de camundongos. O efeito antinociceptivo de MPF4 (1,0 mmol/kg, i.p.) não foi revertido pelo prétratamento dos animais com ioimbina (0,15 mg/kg, i.p.) ou p-clorofenilalanina etil éster (PCPA; 300 mg/kg, i.p.), mas sim, por naloxona (2,0 mg/kg, i.p.), tanto na nocicepção térmica quanto na nocicepção química. O tratamento dos animais durante um período de 8 dias consecutivos com MPF4 (1,0 mmol/kg, i.p), ao contrário daqueles tratados com morfina (5,0 mg/kg, i.p.), não desenvolveram tolerância antinociceptiva nem tolerância cruzada com os animais tolerantes à morfina. Porém, similar ao opióide morfina (11 mg/kg, i.p.), MPF4 (1,0 mmol/kg, i.p) inibiu o trânsito gastrintestinal de camundongos, sendo este efeito revertido por naloxona (2,5 mg/kg, i.p.). Além disso, diferente de indometacina (0,1 mmol/kg, v.o.), MPF4 (1,0 mmol/kg, v.o.) não induziu lesão gástrica em camundongos. Nenhum dos compostos testados causou alteração na atividade locomotora dos camundongos. Estes achados sugerem que os novos pirazoline metil ésteres avaliados parecem ser promissores para o desenvolvimento de novas drogas analgésicas terapeuticamente relevantes.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-05-04T15:08:33Z No. of bitstreams: 1 fabiobalbinomiguel.pdf: 17785036 bytes, checksum: 49c69e67c12d3558b393617795b80d6e (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-05-17T13:31:50Z (GMT) No. of bitstreams: 1 fabiobalbinomiguel.pdf: 17785036 bytes, checksum: 49c69e67c12d3558b393617795b80d6e (MD5) / Made available in DSpace on 2017-05-17T13:31:50Z (GMT). No. of bitstreams: 1 fabiobalbinomiguel.pdf: 17785036 bytes, checksum: 49c69e67c12d3558b393617795b80d6e (MD5) Previous issue date: 2016-07-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Este trabalho descreve a síntese de pirazolinas, hidrazonas, chalconas, enonas e curcuminas, resultando em sessenta e nove novos compostos. O interesse pela obtenção de chalconas, enonas, curcuminas, e de seus análogos sintéticos se deve às inúmeras propriedades farmacológicas descritas para essas classes de compostos. Trinta e sete análogos de chalconas, nove análogos de curcuminas e treze enonas foram obtidos por meio da reação de Claisen Schmidt. Aldeídos e cetonas de cadeia longa foram obtidos via síntese de éteres de Williamson. Dezesseis chalconas tiveram sua atividade esquistossomicida in vitro avaliada frente a vermes adultos de Schistosoma mansoni. Os resultados demostraram que algumas delas foram capazes de causar a morte e a redução na atividade motora em 100% dos parasitos. As pirazolinas sintetizadas foram avaliadas quanto à suas atividades antitubercular, antibacteriana, anti-Trypanosoma cruzi, anticandidal e antitumoral. Um estudo vibracional do tautomerismo a partir dos derivados de pirazolina foi realizado por espectroscopia Raman na forma sólida e em solução de CHCl3, sugerindo a existência de tautômeros, no estado sólido ou em solução. / This work describes the synthesis of pyrazolines, hydrazones, chalcones, enones and curcumines, resulting in sixty-nine new compounds. The interest in obtaining chalcones, enones, curcumines, and their synthetic analogues is due to numerous pharmacological properties described for these classes of compounds. Thirty-seven chalcone, nine curcumin analogues and thirteen enones were obtained via a Claisen-Schmidt reaction. Long-chain aldehydes and ketones were obtained via Williamson ether synthesis. Sixteen chalcone derivatives were evaluated in vitro for their schistosomicidal activity. The results showed that some compounds were able to cause death and reduction in motor activity in 100% of the parasites. The synthesized pyrazolines were evaluated for their antitubercular, antibacterial, anti-Trypanosoma cruzi, anticandidal, antitumor activities. A vibrational study of tautomerism from pyrazoline derivatives has been performed by Raman spectroscopy in solid form and CHCl3 solution. This study suggests the existence of tautomers, in the solid state or in solution.

Une synthèse racémique organocatalytique de pyrazolines 3,5-diaryl a été développée, grâce à l'utilisation d'une guanidine comme catalyseur. Ensuite, une synthèse énantiosélective de n-boc pyrazolines 3,5-diaryl a été mise au point sous catalyse par transfert de phase, atteignant des excès énantiomériques jusqu'à 94 %. Des réactions de transprotection du groupement Boc ont permis l'accès à une variété de substituants sur l'azote N1 de la pyrazoline. Ces développements ont été exploités dans la synthèse d'une pyrazoline biologiquement active. Nous avons exploité un biopolymère chiral, le chitosane, en aminocatalyse, comme organocatalyseur hétérogène. Après mise en forme des modifications chimiques du polymère, les matériaux obtenus ont été testés dans plusieurs réactions organocatalytiques. Un excès énantiomérique de 80 % a été atteint dans une réaction d'aldolisation. Enfin, la technologie de liquide ionique supporté sur chitosane a été appliquée à divers réactions organocatalysées. / An organocatalytic racemic synthesis of 3,5-diaryl pyrazolines was developed, using guanidine as catalyst. Then, an enantioselective synthesis of N-Boc 3,5 diarylpyrazolines under phase transfer catalysis, achieving high enantiomeric excesses up to 94 %. Transprotection reactions of the Boc moiety allowed the introduction of a variety of functional groups on N1 atom of the pyrazolines ring. Finally, we applied this strategy to the synthesis of biologically active pyrazoline. Secondly, we used the chiral biopolymer chitosan in aminocatalysis, as a heterogeneous organocatalyst. We performed chemical modifications either by grafting proline, or by a benzyl moiety leading to secondary polyamines. The obtained materials were tested in different organocatalytic reactions. A 80 % enantiomeric excess has been reached for an aldolisation reaction. Finally, we applied, for the first time, the ionic liquid supported phase strategy on chitossan for aour organocatalysed reactions.

This work presents a crystal chemistry study of seven compounds grouped into three classes: isoxazoles, pyrazoles and pyrazolines here called IPISOX, PRISOX, 4D, OCISOX, C90, B07 e 13B, in order to identify novel acetylcholinesterase inhibitors. The structures of the listed compounds were determined by X-ray diffraction method using monocrystalline samples of the aforementioned substances. The disagreement rates seen between the model and the model defined by the diffraction pattern were: 0.0708; 0.0399; 0.0513; 0.0562; 0.0726; 0.0519; 0.0457 to IPISOX, PRISOX, OCISOX, 4D, B07, 13B e C90, respectively. A appendix refers to several methods involved in the process of recrystallization was attached to work, since it received 13 of the 16 substances to study were improperly to be subjected to the technique of Xray diffraction. To obtain factors responsible for the stability of the lens system were carried Closed Layer Interactions Analysis (ICF). The average values of delocalized electron energies determined in kcal.mol-1 were: 19.00 (IPISOX) ; 23.00 (PRISOX) ; 12.00 (OCISOX and B07) ; 9.00 (4D) ; 6,00 (13B) and 5.00 (C90) . Such relocations are from electronic transitions of the type n * (donor receiver). Other electronic relocation of C-N *O-H and C-H *O-H were also observed for some compounds. However, the first mentioned are relevant to the stability of the electron lens packaging. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Este trabalho apresenta um estudo cristaloquímico de sete compostos agrupados em três classes: isoxazóis, pirazóis e pirazolinas aqui denominados de IPISOX, PRISOX, 4D, OCISOX, C90, B07 e 13B, no intuito de identificar novos inibidores da Acetilcolinesterase. As estruturas dos compostos mencionados foram determinadas por método de difração de Raios X usando amostras monocristalinas das substâncias mencionadas anteriormente. Os índices de discordância verificado entre o modelo proposto e o modelo definido pelo padrão de difração foram: 0,0708; 0,0399; 0,0513; 0,0562; 0,0726; 0,0519; 0,0457 para IPISOX, PRISOX, OCISOX, 4D, B07, 13B e C90, respectivamente. Um apêndice referente aos diversos métodos envolvidos no processo de recristalização foi anexado ao trabalho, uma vez que 13 das 16 substâncias recebidas para estudo estavam em forma inadequada para serem submetidas à técnica de difração de raios X. Visando obter fatores responsáveis pela estabilidade do sistema cristalino foram realizadas Análises de Interações de Camada Fechada (ICF). Os valores médios das energias de deslocalização eletrônica determinados, em kcal.mol-1, foram: 19,00 kcal.mol-1 (IPISOX); 23,00 (PRISOX); 12,00 (OCISOX E B07); 9,00 (4D); 6,00 (13B) E 5,00 (C90). Tais deslocalizações são oriundas de transições eletrônicas do tipo n * (doador receptor). Outras deslocalizações eletrônicas do tipo C-N *O-H e C-H *O-H também foram observadas para alguns compostos. No entanto, as primeiras mencionadas são relevantes para a estabilidade eletrônica do empacotamento cristalino.

No description available.