QSAR Modeling of a Set of Pyrazinoate Esters as Antituberculosis Prodrugs

Tuberculosis is an infection caused mainly by Mycobacterium tuberculosis. A first-line antimycobacterial drug is pyrazinamide (PZA), which acts partially as a prodrug activated by a pyrazinamidase releasing the active agent, pyrazinoic acid (POA). As pyrazinoic acid presents some difficulty to cross the mycobacterial cell wall, and also the pyrazinamide-resistant strains do not express the pyrazinamidase, a set of pyrazinoic acid esters have been evaluated as antimycobacterial agents. In this work, a QSAR approach was applied to a set of forty-three pyrazinoates against M. tuberculosis ATCC 27294, using genetic algorithm function and partial least squares regression (WOLF 5.5 program). The independent variables selected were the Balaban index (I), calculated n-octanol/water partition coefficient (ClogP), van-der-Waals surface area, dipole moment, and stretching-energy contribution. The final QSAR model (N = 32, r(2) = 0.68, q(2) = 0.59, LOF = 0.25, and LSE = 0.19) was fully validated employing leave-N-out cross-validation and y-scrambling techniques. The test set (N = 11) presented an external prediction power of 73%. In conclusion, the QSAR model generated can be used as a valuable tool to optimize the activity of future pyrazinoic acid esters in the designing of new antituberculosis agents.

Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides

A series of 53 nitro derivatives rationally designed were obtained by parallel synthesis and screened against Leishmania donovani. Six compounds exhibited IC(50) values lower than standard drugs. Brief SAR analysis revealed that substitution is important to the activity. Nitrothiophene analogues were more potent than the nitrofuran ones. This was attributed to the ability of sulfur atoms in accommodating electrons from nitro group, which facilitate its reduction and therefore the formation of free radicals lethal to parasites. (c) 2008 Elsevier Ltd. All rights reserved.

Examination into the accuracy of exchangeable cation measurement in saline soils

Despite the increasing prevalence of salinity world-wide, the measurement of exchangeable cation concentrations in saline soils remains problematic. Two soil types (Mollisol and Vertisol) were equilibrated with a range of sodium adsorption ratio (SAR) solutions at various ionic strengths. The concentrations of exchangeable cations were then determined using several different types of methods, and the measured exchangeable cation concentrations compared to reference values. At low ionic strength (low salinity), the concentration of exchangeable cations can be accurately estimated from the total soil extractable cations. In saline soils, however, the presence of soluble salts in the soil solution precludes the use of this method. Leaching of the soil with a pre-wash solution (such as alcohol) was found to effectively remove the soluble salts from the soil, thus allowing the accurate measurement of the effective cation exchange capacity (ECEC). However, the dilution associated with this pre-washing increased the exchangeable Ca concentrations while simultaneously decreasing exchangeable Na. In contrast, when calculated as the difference between the total extractable cations and the soil solution cations, good correlations were found between the calculated exchangeable cation concentrations and the reference values for both Na (Mollisol: y=0.873x and Vertisol: y=0.960x) and Ca (Mollisol: y=0.901x and Vertisol: y=1.05x). Therefore, for soils with a soil solution ionic strength greater than 50 mM (electrical conductivity of 4 dS/m) (in which exchangeable cation concentrations are overestimated by the assumption they can be estimated as the total extractable cations), concentrations can be calculated as the difference between total extractable cations and soluble cations.

Marine nematocides: Tetrahydrofurans from a southern Australian brown alga, Notheia anomala.

Chemical analysis of N. anomala collected off rock platforms along the southern coast of Australia yielded a cis-dihydroxytetrahydrofuran (2), the structure for which was assigned by spectroscopic analysis, chemical derivatization and biomimetic synthesis. Tetrahydrofurans from Notheia anomola are reported for the first time as potent and selective inhibitors of the larval development of parasitic nematodes. SAR observations are made on a selection of natural, semi-synthetic and synthetic tetrahydrofurans. (C) 1998 Elsevier Science Ltd. All rights reserved.

Heterogeneous distribution of isoactins in cultured vascular smooth muscle cells does not reflect segregation of contractile and cytoskeletal domains

We have previously demonstrated that or-smooth muscle (alpha -SM) actin is predominantly distributed in the central region and beta -non-muscle (beta -NM) actin in the periphery of cultured rabbit aortic smooth muscle cells (SMCs). To determine whether this reflects a special form of segregation of contractile and cytoskeletal components in SMCs, this study systematically investigated the distribution relationship of structural proteins using high-resolution confocal laser scanning fluorescent microscopy. Not only isoactins but also smooth muscle myosin heavy chain, alpha -actinin, vinculin, and vimentin were heterogeneously distributed in the cultured SMCs. The predominant distribution of beta -NM actin in the cell periphery was associated with densely distributed vinculin plaques and disrupted or striated myosin and ol-actinin aggregates, which may reflect a process of stress fiber assembly during cell spreading and focal adhesion formation. The high-level labeling of alpha -SM actin in the central portion of stress fibers was related to continuous myosin and punctate alpha -actinin distribution, which may represent the maturation of the fibrillar structures. The findings also suggest that the stress fibers, in which actin and myosin filaments organize into sar-comere-like units with alpha -actinin-rich dense bodies analogous to Z-lines, are the contractile vimentin structures of cultured SMCs that link to the network of vimentin-containing intermediate alpha -actinin filaments through the dense bodies and dense plaques.

Determination of the stability constants of mercury(II) complexes of mixed donor macrobicyclic encapsulating ligands

The reactions of mercury(II) with the mixed donor encapsulating ligands 3,6,16-trithia-6,11,19-triazabicyclo[6.6.6]icosane (AMN(3)S(3)sar) and 1-amino-8-methyl-6,19-dithia-3,10,13,16-tetraazabicyclo[6.6.6]icosane (AMN(4)S(2)sar) have been studied. NMR ligand-ligand competition experiments with the ligands 1,4,8,11-tetraazaeyclotetradecane ([14]aneN(4)), 1-thia-4,7,10-triazacyclododecane ([12]aneN(3)S) and ethylenediaminetetraacetic acid (EDTA) with AMN(3)S(3)sar and Hg(II) indicated that [14]aneN(4) would be an appropriate competing ligand for the, determination of the Hg(II) stability constant. Calculations indicated the ratio of concentrations of AMN3S3sar, [14]aneN(4) and Hg(II) required for the determination of the stability constant ranged from 1:1:1 to 1:5:1. Refinement of the titration curves yielded log(10)K[Hg(AMN(3)S(3)sar)](2+) = 17.7. A similar competition titration resulted in the determination of the stability constant for the AMN(4)S(2)sar system as log(10)K[Hg(AMN(4)S(2)sar)](2+) = 19.5. The observed binding constants for the mixed N/S donor systems and the hexaaza analogues sar (3,6,10,13,16,19-hexaazabicyclo [6.6.6]icosane) and diamsar (1,8-diamino-3,6,10,13,16,19 -hexazabicyclo [6.6.6] icosane (log(10)K-[Hg(diamsar)](2+) = 26.4; log(10)K[Hg(sar)](2+) = 28.1) differ by approximately ten orders of magnitude. The difference is ascribed not to a cryptate effect but to a mismatch in the Hg-N and Hg-S bond lengths in the N/S systems.

Surface foam film waves studied with high-speed linescan camera

Dynamic foam films have been investigated using an improved experimental set-up with a CCD high-speed linescan camera in conjunction with the Scheludko micro-interferometric cell for studying the drainage and rupture of liquid foam films. The improved experimental set-up increased the sensibility of detection of the local thickness heterogeneities and domains during the film evolution. The evolution of the foam films up to the formation of black spots was recorded in the time intervals of 50ms. The wavelengths of the propagating surface waves and their frequencies were determined experimentally. The experimental results show that the current quasi-static hydrodynamic theory does not properly describe the wave dynamics with inter-domain channels. However, the thermodynamic condition for formation of black spots in the foam films was met by the experimental results. (c) 2005 Elsevier B.V. All rights reserved.

Satellite observation and climate system model simulation of the St. Lawrence Island polynya

The St. Lawrence Island polynya (SLIP) is a commonly occurring winter phenomenon in the Bering Sea, in which dense saline water produced during new ice formation is thought to flow northward through the Bering Strait to help maintain the Arctic Ocean halocline. Winter darkness and inclement weather conditions have made continuous in situ and remote observation of this polynya difficult. However, imagery acquired from the European Space Agency ERS-1 Synthetic Aperture Radar (SAR) has allowed observation of the St. Lawrence Island polynya using both the imagery and derived ice displacement products. With the development of ARCSyM, a high resolution regional model of the Arctic atmosphere/sea ice system, simulation of the SLIP in a climate model is now possible. Intercomparisons between remotely sensed products and simulations can lead to additional insight into the SLIP formation process. Low resolution SAR, SSM/I and AVHRR infrared imagery for the St. Lawrence Island region are compared with the results of a model simulation for the period of 24-27 February 1992. The imagery illustrates a polynya event (polynya opening). With the northerly winds strong and consistent over several days, the coupled model captures the SLIP event with moderate accuracy. However, the introduction of a stability dependent atmosphere-ice drag coefficient, which allows feedbacks between atmospheric stability, open water, and air-ice drag, produces a more accurate simulation of the SLIP in comparison to satellite imagery. Model experiments show that the polynya event is forced primarily by changes in atmospheric circulation followed by persistent favorable conditions: ocean surface currents are found to have a small but positive impact on the simulation which is enhanced when wind forcing is weak or variable.

Spin-orbit mixing and nephelauxetic effects in the electronic spectra of nickel(II)-encapsulating complexes involving nitrogen and sulfur donors

A study of spin-orbit mixing and nephelauxetic effects in the electronic spectra of nickel(II)-encapsulating complexes involving mixed nitrogen and sulfur donors is reported. As the number of sulfur donors is systematically varied through the series [Ni(N6-xSx)](2+) (x = 0-6), the spin-forbidden (3)A(2)g --> E-1(g) and (3)A(2g) --> (1)A(1g) transitions undergo a considerable reduction in energy whereas the spin-allowed transitions are relatively unchanged. The [Ni(diAMN(6)sar)](2+) and [Ni(AMN(5)Ssar)](2+) complexes exhibit an unusual band shape for the (3)A(2g) --> T-3(2g) transition which is shown to arise from spin-orbit mixing of the E spin-orbit levels associated with the E-1(g) and T-3(2g) states. A significant differential nephelauxetic effect also arises from the covalency differences between the t(2g) and e(g) orbitals with the result that no single set of Racah B and C interelectron repulsion parameters adequately fit the observed spectra. Using a differential covalency ligand-field model, the spectral transitions are successfully reproduced with three independent variables corresponding to 10Dq and the covalency parameters f(t) and f(e), associated with the t(2g) and e(g) orbitals, respectively. The small decrease in f(t) from unity is largely attributed to central-field covalency effects whereas the dramatic reduction in f(e) with increasing number of sulfur donors is a direct consequence of the increased metal-ligand covalency associated with the sulfur donors. Covalency differences between the t(2g) and e(g) orbitals also result in larger 10Dq values than those obtained simply from the energy of the (3)A(2g) --> T-3(2g) spin-allowed transition.

Structure activity relationship, acute toxicity and cytotoxicity of antimycobacterial neolignan analogues

Objectives The study`s aims were to evaluate the antimycobacterial activity of 13 synthetic neolignan analogues and to perform structure activity relationship analysis (SAR). The cytotoxicity of the compound 2-phenoxy-1-phenylethanone (LS-2, 1) in mammalian cells, such as the acute toxicity in mice, was also evaluated. Methods The extra and intracellular antimycobacterial activity was evaluated on Mycobacterium tuberculosis H37Rv. Cytotoxicity studies were performed using V79 cells, J774 macrophages and rat hepatocytes. Additionally, the in-vivo acute toxicity was tested in mice. The SAR analysis was performed by Principal Component Analysis (PCA). Key findings Among the 13 analogues tested, LS-2 (1) was the most effective, showing promising antimycobacterial activity and very low cytotoxicity in V79 cells and in J774 macrophages, while no toxicity was observed in rat hepatocytes. The selectivity index (SI) of LS-2 (1) was 91 and the calculated LD50 was 1870 mg/kg, highlighting the very low toxicity in mice. SAR analysis showed that the highest electrophilicity and the lowest molar volume are physical-chemical characteristics important for the antimycobacterial activity of the LS-2 (1). Conclusions LS-2 (1) showed promising antimycobacterial activity and very weak cytotoxicity in cell culture, as well as an absence of toxicity in primary culture of hepatocytes. In the acute toxicity study there was an indication of absence of toxicity on murine models, in vivo.

Antagonism by NKP608 of substance P-induced plasma protein exudation in a novel preparation of perfused trachea in rats and guinea-pigs in vivo

Objective: To examine whether NKP608, a novel 1-benzoyl-2-benzyl-4-aminopiperidine NK1 receptor antagonist, inhibits substance P (SP)-induced airway plasma protein exudation in vivo. Material: Anaesthetised English shorthair guinea-pigs and Wistar rats. Treatment: Tachykinin peptides were applied topically onto the trachea and antagonists administered intravenously. Methods: Tracheal segments isolated in situ were perfused with saline and plasma-derived protein assayed in the perfusate. Results: SP (1 muM) caused plasma protein exudation, which was abolished by an NK1 antagonist (RP 67580, 1.75 mumol/kg) but unaffected by an NK2 antagonist (SR 48968, 1.75 mumol/kg) indicating the response is NK1-receptor-mediated. This was confirmed with a response to an NK1 agonist ([Sar(9), Met(O-2)(11)]-SP, 1 muM) but none to an NK2 agonist ([betaAla(8)]-neurokinin A(4-10), 1 muM). NKP608 inhibited SP responses with estimated ID50 values (mumol/kg) of 0.0044 (guinea-pigs) and 0.19 (rats). Conclusions: NKP608 is an antagonist in vivo of NK1 receptor-induced tracheal plasma protein exudation and is more potent in guinea-pigs than rats.

Gest??o por compet??ncias em organiza????es de governo

Ao longo dos ??ltimos anos vem se ampliando os espa??os e o interesse, no meio acad??mico e empresarial, pelas discuss??es sobre uso da abordagem da compet??ncia como marco importante para as atividades de gest??o de recursos humanos. A difus??o dessa abordagem entre as organiza????es p??blicas brasileiras ??, entretanto, bem mais recente, e conta, ainda hoje, com um n??mero insuficiente de estudos e publica????es. ?? esta a raz??o da import??ncia e pertin??ncia da publica????o do livro " Gest??o por compet??ncias em organiza????es de governo"

A seguridade social no Brasil e os obst??culos institucionais ?? sua implementa????o

An??lise hist??rico-administrativa da forma????o do sistema de seguridade social no Brasil, enfatizando alguns dos principais aspectos condicionantes da sua gest??o. Registra as id??ias-for??a do modelo de prote????o social adotado em 1988, contextualizadas no processo de evolu????o das pol??ticas sociais de Estado; descreve e discute os problemas constatados na operacionaliza????o recente das pol??ticas p??blicas de sa??de, assist??ncia e previd??ncia social, vistas sob a ??tica dos seus processos de planejamento e or??amenta????o, das estruturas organizacionais formais e das pr??ticas diretivas e de controle, e da articula????o intergovernamental, conduzindo ?? avalia????o de desempenho do sistema atual e a propostas da sua consolida????o, com base nos princ??pios de descentraliza????o, controle social e manuten????o de um permanente processo de avalia????o institucional.

Gerenciamento da qualidade total do INSS

A experi??ncia por n??s vivenciada no projeto piloto de Gerenciamento pela Qualidade Total, refor??a positivamente a nossa convic????o de que ?? poss??vel implementar esta mudan??a de cultura no SERVI??O P??BLICO, expandindo o projeto, por etapas, em todo o pa??s. Que esta mudan??a ?? centrada nas pessoas e que depende fundamentalmente do estabelecimento de uma VIS??O COMUM de Institui????o, de uma lideran??a que conquiste o comprometimento dos servidores e que crie espa??o para a valoriza????o das pessoas e o reconhecimento aos resultados atingidos

Texto para discuss??o 25: desafios e oportunidades no setor de compras governamentais na Am??rica Latina e Caribe: o caso brasileiro

Este texto tem como objetivo apresentar um panorama geral do setor de compras governamentais na Am??rica Latina, passando posteriormente a uma an??lise do caso brasileiro. Inicialmente s??o abordados alguns aspectos da evolu????o do Estado, demonstrando que as grandes altera????es no perfil do setor p??blico n??o significam obrigatoriamente uma redu????o do tamanho do Estado na Am??rica Latina, mas sim uma profunda transforma????o na organiza????o da sua a????o. No continente latino-americano, o setor de compras tem sido objeto de debates e acordos que visam uma converg??ncia das regras dos pa??ses que integrar??o a ALCA ??? ??rea de Livre Com??rcio das Am??ricas. Este texto tamb??m aborda as principais tend??ncias, desafios e oportunidades neste processo.Na apresenta????o do caso brasileiro s??o analisadas as pol??ticas, o modelo de gest??o e a tecnologia aplicada no setor de compras do governo central, finalizando com uma aprecia????o da nova proposta de lei para o setor.