Conformational Polymorphism in Racemic Crystals of the Diuretic Drug Chlortalidone

Chlortalidone (HIGROTON) is a diuretic drug widely used in antihypertensive therapy. Thus far, only two solid-state polymorphs of chlortalidone have been reported. We elucidated the structure of chlortalidone form I and a new polymorph. This new phase, namely, chlortalidone form III, was also entirely characterized. It was possible to conclude that it is a conformer with a different orientation of the chlorobenzenesulfonamide moiety. Compared to form I, it has a rotation of about 90 degrees on the axis of the C-C bond bridging the substituted phenyl and isoindolinyl rings. This conformational feature is related to the crystal packing patterns of the chlortalidone forms. Furthermore, certain intermolecular hydrogen bonds are present in both polymorphs, giving rise to ribbons with chlortalidone enantiomers alternately placed into them. The chlortalidone form I and form III crystallize in the triclinic space group P (1) over bar as racemic mixtures. Additional conformational details also differentiate the chlortalidone conformers. Slight twists on the isoindolinyl and sulfamyl groups exist. Considering all structural relationships, the fingerprint plots derived from the Hirshfeld surfaces exhibited the characteristics of the chlortalidone form I and form III crystal structures.

Triple Structural Transition below Room Temperature in the Antifilarial Drug Diethylcarbamazine Citrate

A very unusual triple structural transition pattern below room temperature was observed for the antifilarial drug diethylcarbamazine citrate. Besides the first thermal, crystallographic, and vibrational investigations of this first-line drug used in clinical treatment for lymphatic filariasis, a noteworthy behavior with three structural transformations as a function of temperature was demonstrated by differential scanning calorimetry, Raman spectroscopy, and single-crystal X-ray diffractometry. Our X-ray data on single crystals allow for a complete featuring and understanding of all transitions, since the four structures associated with the three solid-solid phase transformations were accurately determined. Two of three structural transitions show an order-disorder mechanism and temperature hysteresis with exothermic peaks at 224 K (T(1)`) and 213 K (T(2)`) upon cooling and endothermic ones at 248 K (T(1)) and 226 K (T(2)) upon heating. The other transition occurs at 108 K (T(3)) and it is temperature-rate sensitive. Molecular displacements onto the (010) plane and conformational changes of the diethylcarbamazine backbone as a consequence of the C-H center dot center dot center dot N hydrogen bonding formation/cleavage between drug molecules explain the mechanism of the transitions at T(1)`/T(2). However, such changes are observed only on alternate columns of the drug intercalated by citrate chains, which leads to a doubling of the lattice period along the a axis of the 235 K structure with respect to the 150 and 293 K structures. At T(2)`/T(1), these structural alterations occur in all columns of the drug. At T(3), there is a rotation on the axis of the N-C bond between the carbamoyl moiety and an ethyl group of one crystallographically independent diethylcarbamazine molecule besides molecular shifts and other conformational alterations. The impact of this study is based on the fascinating finding in which the versatile capability of structural adaptation dependent on the thermal history was observed for a relatively simple organic salt, diethylcarbamazine citrate.

A theoretical and mass spectrometry study of the fragmentation of mycosporine-like amino acids

In the present study, the mycosporine-like amino acids (MAAs) were isolated from the marine red alga Gracilaria tenuistipitata and analysed by high-resolution accurate-mass sequential mass spectrometry (MSn). In addition to the proposed fragmentation mechanism based on the MSn analysis, it is clearly demonstrated that the elimination of mass 15 is a radical processes taking place at the methoxyl substituent of the double bond. This characteristic loss of a methyl radical was studied by theoretical calculations and the homolytic cleavage of the O-C bond is suggested to be dependent on the bond weakening. The protonation site of the MAAs was indicated by analysis of the Fukui functions and the relative Gibbs energies of the several possible protonated forms. (C) 2008 Elsevier B.V. All rights reserved.

Spectroscopic evidences of the presence of hydrogenated species on the surface of copper during CO(2) electroreduction at low cathodic potentials

Carbon dioxide electroreduction on copper electrode was studied by surface enhanced Raman scattering (SERS) in K(2)SO(4) aqueous solutions with different pH values. CO(2) was bubbled into the solution at 0 V vs. Ag/AgCl, i.e., on an oxidized copper surface. In acidic solutions (pH around 2.5), at -0.2 V, bands indicative of the presence of ethylene on the electrode surface were detected. Although ethylene is knowledgably a product of CO(2) electroreduction on copper, it was not experimentally identified on the electrode`s surface at such a low cathodic potential in prior works. In solutions with pH around 2.5, CO bands were not observed, suggesting that hydrocarbons could be formed by a pathway that does not occur via adsorbed CO. In solutions with higher pHs, a complex spectral pattern, between 800 and 1700 cm(-1), was observed at approximately -0.4 V. The observed spectrum closely resembles those reported in the literature for adsorption of monocarboxylic acids with small chains. The spectral features indicate the presence of a structure containing a double C=C bond. a carboxyl group, and C-H bonds on the electrode`s surface. SERS spectra obtained in CO-saturated solution are also presented. However, in this case, no SERS bands were observed in the region between 800 and 1700 cm(-1) at low cathodic potentials. (c) 2009 Elsevier B.V. All rights reserved.

Spectroscopic and electrochemical properties of iron(II) complexes of polydentate Schiff bases containing pyrazine, pyridine and imidazole groups

We report the synthesis and spectroscopic/electrochemical properties of iron(II) complexes of polydentate Schiff bases generated from 2-acetylpyridine and 1,3-diaminopropane, acetylpyrazine and 1,3-diaminopropane, and from 2-acetylpyridine and L-histidine. The complexes exhibit bis(diimine)iron(II) chromophores in association with pyrazine, pyridine or imidazole groups displaying contrasting pi-acceptor properties. In spite of their open geometry, their properties are much closer to those of macrocyclic tetraimineiron(II) complexes. An electrochemical/spectroscopic correlation between E degrees(Fe(III/II)) and the energies of the lowest MLCT band has been observed, reflecting the stabilization of the HOMO levels as a consequence of the increasing backbonding effects in the series of compounds. Mossbauer data have also confirmed the similarities in their electronic structure, as deduced from the spectroscopic and theoretical data. (C) 2008 Elsevier B.V. All rights reserved.

Ethanol electro-oxidation on carbon-supported Pt-Ru, Pt-Rh and Pt-Ru-Rh nanoparticles

This work investigates the effects of carbon-supported Pt, Pt-Ru, Pt-Rh and Pt-Ru-Rh alloy electrocatalysts oil the yields of CO2 and acetic acid as electro-oxidation products of ethanol. Electronic and structural features of these metal alloys were studied by in situ X-ray absorption spectroscopy (XAS). The electrochemical activity was investigated by polarization experiments and the reaction intermediates and products were analyzed by in situ Fourier Transform Infra-Red Spectroscopy (FTIR). Electrochemical stripping of CO. which is one of the adsorbed intermediates, presented a faster oxidation kinetics on the Pt-Ru electrocatalyst, and similar rates of reaction on Pt-Rh and Pt. The electrochemical current of ethanol oxidation showed a higher value and the onset potential was less positive oil Pt-Ru. However, in situ FTIR spectra evidenced that the CO2/acetic acid ratio is higher for the materials with Rh, mainly at lower potentials. These results indicate that the Ru atoms act mainly by providing oxygenated species for the oxidation of ethanol intermediates, and point out ail important role of Rh on the C-C bond dissociation. (C) 2007 Elsevier Ltd. All rights reserved.

Towards to the trans-bromination of 2-styrylpyridine with a palladacycle intermediary and structure analysis for trans-1,2-dibromo-2-styrylpyridine

The simple halogenation of alkynes in conventional organic reactions gives a blend of cis and trans isomers. It is proposed then, a synthesis of stereospecific halogenation of alkynes in trans position, using palladacycle as intermediaries. The recrystallization of the compound obtained by bromination of 2-Styrylpyridine, with cyclepalladium intermediary results in a single crystal, which is subjected to X-ray diffraction. The crystal packing is established through weak interactions of three types. The first one is of the type pi x pi interactions, from symmetry operation, between the centroids. The second one is of the type C-X center dot center dot center dot pi interactions. And the last type is an anomalous intermolecular interaction between halogens, C-X center dot center dot center dot X-C, with bond distances smaller than the sum of the van der Waals radii. The conformation on the C=C bond is trans and the dihedral angle between the aromatic rings is (with esd approximate) 18.1(3)degrees. (C) 2010 Elsevier B.V. All rights reserved.

Methanol and ethanol electro-oxidation on Pt-SnO(2) and Pt-Ta(2)O(5) sol-gel-modified boron-doped diamond surfaces

The search for more efficient anode catalyst than platinum to be used in direct alcohol fuel cell systems is an important challenge. In this study, boron-doped diamond film surfaces were modified with Pt, Pt-SnO(2) and Pt-Ta(2)O(5) nano-crystalline deposits by the sol-gel method to study the methanol and ethanol electro-oxidation reactions in acidic medium. Electrochemical experiments carried out in steady-state conditions demonstrate that the addition of SnO(2) to Pt produces a very reactive electrocatalyst that possibly adsorbs and/or dissociate ethanol more efficiently than pure Pt changing the onset potential of the reaction by 190 mV toward less positive potentials. Furthermore, the addition of Ta(2)O(5) to Pt enhances the catalytic activity toward the methanol oxidation resulting in a negative shift of the onset potential of 170 mV. These synergic effects indicate that the addition of these co-catalysts inhibits the poisoning effect caused by strongly adsorbed intermediary species. Since the SnO(2) catalyst was more efficient for ethanol oxidation, it could probably facilitate the cleavage of the C-C bond of the adsorbed intermediate fragments of the reaction. (C) 2009 Elsevier B.V. All rights reserved.

Síntese e análise estrutural de novos ciclopaladatos e síntese de N-heterociclos a partir de ciclopaladatos e alenos

Os compostos de paládio vêm apresentado uma vasta linha de aplicação, tanto como catalisadores como precursores em reações de síntese orgânica. Dentre esses compostos, os ciclopaladatos, que são compostos cíclicos com uma ligação Pd-heteroátomo, permite a formação de novas estruturas cíclicas contendo algum heteroátomo, como nitrogênio, oxigênio ou enxofre. Neste trabalho foram sintetizadas aminas propargílicas capazes de se coordenar a sais de paládio, formando novos ciclopaladatos através da reação de cloropaladação. Esses compostos se encontram na forma de dímeros e podem apresentar-se como diferentes isômeros. Estudos espectroscópicos, tais como RMN de 1H, 13C e raios-X de monocristais foram realizados para a elucidação estrutural desses novos compostos. Além dos isômeros geométricos clássicos (cisóide e transóide) foram observados pela primeira vez a formação de atropoisômeros. Esses ciclopaladatos, contendo nitrogênio ligado ao paládio, foram testados frente a alenos diferentemente substituídos, mostrando que ocorre a inserção do aleno na ligação Pd-C e, seguido da depaladação, ocorre a formação de novos compostos heterocíclicos a seis membros. Alguns ciclopaladatos, quando em solução, podem apresentar certa instabilidade, ocorrendo a decomposição do ciclopaladato com a regeneração do alcino precursor do respectivo ciclopaladato. Assim, estudou-se a reação de decomposição de diferentes ciclopaladatos, chamada de retrocloropaladação, utilizando a técnica de RMN de 1H em diferentes intervalos de tempo.

Um estudo sobre os determinantes do prêmio de risco da dívida pública no Brasil

O objetivo deste trabalho é identificar os determinantes do prêmio de risco da dívida pública no Brasil, uma vez que a redução deste permitirá que as taxas de juros na economia brasileira sejam compatíveis com um maior crescimento econômico. Os resultados empíricos obtidos não rejeitam as hipóteses dos modelos de Dornbusch (1983), e sua posterior extensão ao caso italiano por Cottarelli, C. e Mecagni, M. (1990), e de Romer (2000), de que uma melhora dos fundamentos econômicos reduz o prêmio de risco da dívida pública. Em particular, concluímos que as variáveis relacionadas a indicadores fiscais explicam os movimentos da medida de prêmio de risco utilizada, o spread over treasury do C-bond.

Ensaios em macroeconometria e finanças

Esta tese de doutorado está composta por quatro ensaios em macroeconometria e finanças com aplicações nas áreas de abertura comercial, custo de bem estar do ciclo de negócios e taxas de juros. No primeiro ensaio analisamos o comportamento da indústria de transformação após as reformas implantadas na década de noventa. Verificamos se o processo de abertura gerou aumentos da produtividade média da indústria de transformação. Adicionalmente, estimamos o mark-up de diferentes setores industriais e testamos se este se modifica após a abertura comercial. Os resultados das estimações indicam a existência de um significativo aumento na produtividade industrial na maior parte dos setores estudados. O canal para este aumento de produtividade, aparentemente, não é o aumento da concorrência, já que não há evidência estatística de redução de mark-up. Este é talvez o resultado mais surpreendente do artigo, o fato de que o mark-up não se modificar significativamente após a abertura comercial. Os setores estimados como não concorrenciais antes da abertura continuaram a ser depois dela. Acesso a insumo importados e uso de novas tecnologias podem ser possíveis canais de aumento de produtividade. Este resultado está em desacordo com Moreira (1999) que constrói diretamente dos dados medidas de mark-up. No segundo ensaio testamos a Hipótese das Expectativas Racionais (HER) para a estrutura a termo brasileira. Examinamos várias combinações de prazos entre 1 dia e 1 ano, seguindo a metodologia adotada pelo Banco Central do Brasil, para o período de Julho de 1996 a Dezembro de 2001. Mostramos que: (i) os coeficientes estimados dos diferenciais de rendimento entre as taxas longa e curta (yield spreads) nas equações de mudança de curto prazo da taxa longa e nas equações de mudança de longo prazo da taxa curta são imprecisos e incapazes de rejeitarem a HER; e (ii) diferenciais de rendimento altamente correlacionados com as previsões de expectativas racionais das futuras mudanças das taxas curtas, mas significativamente mais voláteis que estas últimas, sugerem a rejeição da HER. A hipótese alternativa de reação exagerada (overreaction) do diferencial de rendimento em relação à expectativa das futuras variações da taxa curta parece uma explicação razoável para as evidências, com implicações para a política monetária e para a gestão de investimentos. No terceiro ensaio estudamos o custo de bem-estar dos ciclos de negócios. Robert Lucas (1987) mostrou um resultado surpreendente para a literatura de ciclos de negócios, o custo de bem-estar, por ele calculado, é muito pequeno (US$ 8,50 por ano). Modelamos as preferências por funções com elasticidade de substituição constante e uma forma reduzida para o consumo razoável. Construímos dados seculares para a economia americana e computamos o custo de bem-estar para dois períodos distintos, pré e pós-segunda guerra mundial, usando três formas alternativas de decomposição tendência-ciclo, com foco na decomposição de Beveridge-Nelson. O período pós-guerra foi calmo, com um custo de bem-estar que raramente ultrapassa 1% do consumo per-capita (US$ 200,00 por ano). Para o período pré-guerra há uma alteração drástica nos resultados, se utilizamos a decomposição de Beveridge-Nelson encontramos uma compensação de 5% do consumo per-capita (US$ 1.000,00 por ano) com parâmetros de preferências e desconto intertemporal razoáveis. Mesmo para métodos alternativos, como o modelo com tendência linear, encontramos um custo de bem estar de 2% do consumo per-capita (US$ 400,00 por ano). Deste estudo podemos concluir: (i) olhando para dados pós-guerra, o custo de bem-estar dos ciclos de negócios marginal é pequeno, o que depõe contra a intensificação de políticas anticíclicas, sendo que do ponto de vista do consumidor pré-segunda guerra este custo é considerável; e (ii) o custo de bem-estar dos ciclos de negócios caiu de 5% para 0.3% do consumo per-capita, do período pré para o período pós-guerra, se esta redução é resultado de políticas anticíclicas, estas políticas foram muito bem sucedidas. Por último, no quarto ensaio analisamos o comportamento da taxa de juros livre de risco - cupom cambial - na economia brasileira para o período de 20 de janeiro de 1999 a 30 de julho de 2003. Identificamos os componentes de curto e longo prazo de três medidas de taxa de retorno, as quais foram submetidas aos tratamentos econométricos propostos em Vahid e Engle (1993) e Proietti (1997). Os resultados sugerem a convergência das taxas de retorno para um equilíbrio de longo prazo. Identificamos a dominância do componente de longo prazo na determinação da trajetória do Prêmio do C-BOND e do componente de curto prazo no caso do Prêmio do Swap Cambial. Já para o Prêmio Descoberto de Juros não conseguimos identificar o domínio de qualquer componente. Associando o componente de longo prazo aos fundamentos da economia e os componentes de curto prazo a choques nominais, poderíamos dizer que, em termos relativos, o Prêmio do C-BOND estaria mais fortemente ligado aos fundamentos e o Prêmio do Swap Cambial a choques nominais.

The risk premium on brazilian government debt, 1996-2002

The goal of this paper is to identify the determinants of the risk premium on Brazilian government debt. As the risk premium is a component of the interest rate set by the Brazilian central bank, its reduction would make it possible for the central bank to cut interest rates to levels compatible with a higher economic growth environment. The empirical evidence presented in this paper does not reject the hypotheses that fiscal solvency and the size of the public debt affect the risk premium as measured by the spread over treasury bills of the Brazilian C-bond.

A tellurium-based cathepsin B inhibitor: Molecular structure, modelling, molecular docking and biological evaluation

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Theoretical study on the molecular mechanism for the reaction of VO2+ with C2H4

The complex reaction between VO2+ ((1)A(1)/(3)A) and C2H4 (Ag-1(g)/(3)A(1)) to yield VO+ ((1)Delta/(3)Sigma) and CH3CHO ('A'/(3)A) has been studied by means of B3LYP/6-31G* and B3LYP/6-311G(2d,p) calculations. The structures of all reactants, products, intermediates, and transition structures of this reaction have been optimized and characterized at the fundamental singlet and first excited triplet electronic states. Crossing points are localized, and possible spin inversion processes are discussed by means of the intrinsic reaction coordinate approach. Relevant stationary points along the most favorable reaction pathways have been studied at the CCSD/6-311G(2d,p)//B3LYP/6-311G(2d,p) calculation level. The theoretical results allow the development of thermodynamic and kinetic arguments about the reaction pathways of the title process. In the singlet state, the first step is the barrierless obtention of a reactant complex associated with the formation of a V-C bond, while in the triplet state a three-membered ring addition complex with the V bonded to the two C atoms is obtained. Similar behavior is found in the exit channels: the product complexes can be formed from isolated products without barriers. The reactant and product complexes are the most stable stationary points in the singlet and triplet electronic states. From the singlet state reactant complex, two reaction pathways are posssible to reach the triplet state product complex. (i) A mechanism in which a hydrogen transfer process is the first and rate limiting step and the second step is an oxygen transfer between vanadium and carbon atoms with a concomitant change in the spin state. The crossing point between singlet and triplet spin states is not kinetically relevant because it takes place at a later stage occurring in the exit channel. (ii) A mechanism in which the first stage renders a four-membered ring between vanadyl cation and the ethylene fragment and an oxygencarbon bond is formed; on going from this minimum to the second transition structure, associated with a carbon-vanadium bond breaking process, the crossing point between singlet and triplet spin states is reached. The final step is the hydrogen transfer between both carbon atoms to yield the product complex. In this case the spin change opens a lower barrier pathway. The transition structures with larger values of relative energies for both reactive channels of VO2+ ((1)A(1)) + C2H4 (Ag-1) --> VO+ ((3)Sigma) + CH3CHO ((1)A') present similar energies, and the two reaction pathways can be considered as competitive.

Platelet aggregation and TGF-beta(1) plasma levels in pregnant women with preeclampsia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)