Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with high levels of tumour necrosis factor-alpha (TNF-a) in synovial fluid and synovial tissue (Saxne et al., 1989). Thalidomide is a proven inhibitor of the biological synthesis of TNF-a (Sampaio et al., 1991) and is believed to rely on this action for its suppression of the wasting of tissue which accompanies RA. Oral administration of thalidomide has proven to be effective in RA, but unacceptable side effects are easily provoked (Gutierrez-Rodriguez, 1984). Administration of thalidomide via the dermal route can down-regulate TNF-a production in and around the affected joint, and this without raising the systemic blood level to a problematical level. Based on thalidomide's physicochemical properties, it is unlikely that it can be delivered percutaneously at a dose required for RA. Therefore, we have embraced the idea of using N-alkyl analogues of thalidomide. The most important feature that an analogue of this compound might contribute is decreased crystallinity and increased lipophilicity. Ordinarily both these parameters should favour percutaneous delivery. The current study was primarily aimed at exploring the feasibility of percutaneous delivery of thalidomide and subsequently, three of its odd chain IV-alkyl analogues (methyl, propyl and pentyl) via physicochemical characterization and assessment of their innate abilities to diffuse through skin as an initial step towards developing a topical dosage form for the best compound. The biological activities, more specifically their potential to inhibit the production of TNF-a was determined for thalidomide and its N-alkyl analogues. In order to achieve the objectives, the study was undertaken by synthesizing and determining the physicochemical parameters of thalidomide and its N-alkyl analogues. A high level of crystallinity is expressed in the form of a high melting point and heat of fusion. This limits solubility itself, and thus also sets a limit on mass transfer across the skin. Generally, the greater a drug's innate tendency to dissolve, the more likely it is that the drug can be delivered at an appropriate rate across the skin (Ostrenga et al., 1971). Therefore, the melting points and heats of fusion were determined by differential scanning calorimetry. Aqueous solubility and the partition coefficient (relative solubility) are major determinants of a drug's dissolution, distribution and availability. N-octanollwater partition coefficients were determined at pH 6.4. Solubilities in water, a series of n-alcohols and mixed solvents were obtained, as well as the solubility parameters of the compounds in study. Secondly, in vitro permeation studies were performed from these solvents and vehicles using vertical Franz diffusion cells with human epidermal membranes. Thirdly, tumour necrosis factor-alpha (TNF-a) inhibition activities were assessed for thalidomide and its N-alkyl analogues. By adding a methyl group to the thalidomide structure, the melting point drops by over 100°C and, in this particular instance upon increasing the alkyl chain length to five -CH2- units the melting points decrease linearly. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Methylation of the thalidomide molecule enhanced the aqueous solubility 6-fold, but as the alkyl chain length is further extended from methyl to pentyl, the aqueous solubility decreased exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increase in lipophilicity and consequently an increase in solubility in nonpolar media. Log partition coefficients increased linearly with increasing alkyl chain length. Solubilities in a series of n-alcohols, methanol through dodecanol, were found to be in the order of pentyl > propyl > methyl > thalidomide. The N-alkyl analogues have more favourable physicochemical properties than thalidomide to be delivered percutaneously. The in vitro skin permeation data proved that the analogues can be delivered far easier than thalidomide itself. N-methyl thalidomide showed the highest steady-state flux through human skin from water, n-alcohols and combination vehicles. Thalidomide and its N-alkyl analogues were all active as TNF-a inhibitors. Finally, active as a TNF-a inhibitor, N-methyl thalidomide is the most promising candidate to be delivered percutaneously for treatment of rheumatoid arthritis, of those studied. / Thesis (PhD (Pharmaceutics))--PU for CHE, 1999.

DERIVATIVES OF 5-ALKYLPYRAZINE-2-CARBOXYLIC ACID AS POTENTIAL ANTI-INFECTIVES HALÍŘOVÁ MARTINA Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic In our previous study, we have demonstrated that 5-alkylamino-N- phenylpyrazine-2-carboxamides with longer alkyl chain (C5-C8) exerted micromolar growth inhibition activity against M. tuberculosis H37Rv. We speculated that the long alkylamino chain could facilitate the penetration of lipophilic mycobacterial cell envelope. To test this hypothesis, we performed the amino to methylene isosteric exchange and designed a series of 5-alkyl-N-phenylpyrazine-2-carboxamides. 5- Alkylpyrazine-2-carboxylic acids (5-Ak-POA) were prepared by homolytic alkylation of commercially available pyrazine-2-carbonitrile by respective alkanoic acid, followed by hydrolysis of the carbonitrile group. Final derivatives were prepared by CDI mediated coupling of 5-Ak-POA with corresponding aniline at RT. Final compounds were described by melting point, elementary analysis, IR spectroscopy and 1 H, 13 C NMR. Then they were tested in vitro for antimycobacterial activity against M. tuberculosis H37Rv and several non-tuberculous mycobacterial strains. Several compounds exerted MIC of 3.13-6.25 µg mL-1 ....

Submitted by VANESSA GONÇALVES WOLF null (nessa.wolf@hotmail.com) on 2017-07-13T23:39:50Z No. of bitstreams: 1 20170708145234dissertacao_final_vanessa_goncalves_wolf_corrigida_jul_8.pdf: 3123091 bytes, checksum: 0e5f498e0767893a065858a9ae558c1c (MD5) / Approved for entry into archive by Monique Sasaki (sayumi_sasaki@hotmail.com) on 2017-07-14T18:44:45Z (GMT) No. of bitstreams: 1 wolf_vg_me_arafcf.pdf: 3123091 bytes, checksum: 0e5f498e0767893a065858a9ae558c1c (MD5) / Made available in DSpace on 2017-07-14T18:44:45Z (GMT). No. of bitstreams: 1 wolf_vg_me_arafcf.pdf: 3123091 bytes, checksum: 0e5f498e0767893a065858a9ae558c1c (MD5) Previous issue date: 2017-06-22 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Helicobacter pylori é um dos principais causadores de gastrite crônica e úlcera péptica, e embora o mecanismo envolvido na inflamação gástrica por esta bactéria não esteja completamente elucidado, sabe-se do importante papel das espécies reativas de oxigênio (EROs) produzidas por polimorfonucleares neutrófilos, que são atraídos e ativados pelo agente da infecção, sem que, entretanto, consigam debelar a mesma, mas que contribuem fortemente para a lesão tecidual e o processo inflamatório crônico. Diante disso, tem aumentado a busca de novas estratégias de tratamento que possam levar à redução do estresse oxidativo gerado no sítio da infecção, com consequente redução do processo inflamatório. Neste sentido, ácido gálico, juntamente com seus ésteres (galato de metila, propila, hexila e octila), foram utilizados neste estudo, com o objetivo de avaliar suas ações como inibidores da liberação de EROs por neutrófilos ativados, bem como seus efeitos antimicrobianos sobre H. pylori. Para a avaliação da atividade antioxidante dessas substâncias foram realizados ensaios livres de células (efeito supressor sobre o radical DPPH e sobre radicais peroxila), e o efeito anti-EROs foi avaliado utilizando neutrófilos isolados de sangue humano estimulados por H. pylori, Zymosan ou PMA, através de ensaio quimiluminescente dependente de luminol ou lucigenina, ensaio com WST-1, ensaio de inibição da produção de HOCl, e o teste do NBT. Ensaio antimicrobiano foi realizado através da técnica de microdiluição em caldo. A presença da cadeia lateral carbônica levou a um significativo aumento na capacidade dos ésteres em inibir a produção de EROs por neutrófilos ativados, quando comparados ao ácido precursor, com destaque para os galatos de hexila e octila, que inibiram em quase 100% a produção de radical ânion superóxido, bem como de todas as EROs do burst oxidativo de forma geral. Galatos de octila e hexila também mostraram-se ser as moléculas com maior atividade antimicrobiana sobre H. pylori, com um valor de CIM de 125 e 250g/mL, respectivamente, ao passo que as demais substâncias apresentaram valor de CIM acima de 1000 g/mL. Os resultados obtidos mostram o grande potencial dos ésteres do ácido gálico quanto à suas atividades anti-H. pylori e anti-EROs, e além disso demonstram a importância da presença de uma cadeia carbônica lateral, conferindo maior hidrofobicidade à molécula, para obter-se a máxima atividade antimicrobiana in vitro e a máxima atividade antioxidante em modelo ex vivo. Assim, os ésteres do ácido gálico apresentam-se como moléculas promissoras no tratamento da infecção por Helicobacter pylori, apresentando ação antimicrobiana sobre o mesmo, bem como na redução do estresse oxidativo gerado no sítio da infecção. / Helicobacter pylori is one of major cause of chronic gastritis and peptic ulcer disease, and although the mechanism involved in gastric inflammation by this bacterium is not fully understood, it is know the important role of reactive oxygen species (ROS) produced by polymorphonuclear neutrophils (PMNs), which are attracted and activated by infection agent, without, however, to be able to overcome the same, but which contribute strongly to the tissue damage and chronic inflammation. Therefore, it has increased the search for new strategies of treatment that can lead to the reduction of the oxidative stress generated at the infection site, with consequent reduction of the inflammatory process. In this sense, gallic acid, together with its esters (methyl, propyl, hexyl and octyl gallate), were used in this study, with the aim of evaluating their actions as inhibitors of ROS release by activated neutrophils, as well as their antimicrobial effects on H. pylori. Cell-free assays (suppressor effect on the DPPH radical and peroxyl radicals) were performed to evaluate the antioxidant activity of these substances, and the anti-EROs effect was evaluated using neutrophils isolated from human blood, stimulated by H. pylori, Zymosan or PMA, through luminol-dependent or lucigenin-dependent chemiluminescent assay, WST-1 assay, inhibition of HOCl production assay, and the NBT assay. Antimicrobial assay was performed by broth microdilution technique. The presence of the carbonic side chain led to a significant increase in the ability of the esters to inhibit the ROS production by activated neutrophils when compared to the precursor acid, especially hexyl and octyl gallates, which inhibited practically 100% of the superoxide anion radical production, as well as all ROS of the oxidative burst in general. Octyl and hexyl gallates were also shown to be the molecules with the highest antimicrobial activity on H. pylori, with a MIC value of 125 and 250 μg/mL, respectively, while the other substances had a MIC value higher than 1000 g/ml. The results show the great potential of the esters of gallic acid for their anti-H. pylori and anti-EROs activities, and furthermore demonstrate the importance of the presence of a lateral carbonic chain, giving greater hydrophobicity to the molecule, to obtain the maximum antimicrobial activity in vitro and the maximum antioxidant activity in an ex vivo model. Thus, esters of gallic acid are promising molecules in the treatment of Helicobacter pylori infection, presenting antimicrobial action on the same, as well as reducing the oxidative stress generated at the site of infection. / CNPq: 130667/2015-3 / FAPESP: 2015/21693-0

Submitted by Lúcia Bonci Cavalca (l.bonci@hotmail.com) on 2018-04-26T18:08:18Z No. of bitstreams: 1 CAVALCA, LB versão repositorio.pdf: 11866412 bytes, checksum: 0a27e5a7f7f756cb88de16361ad78a27 (MD5) / Approved for entry into archive by Ana Paula Santulo Custódio de Medeiros null (asantulo@rc.unesp.br) on 2018-04-26T19:16:54Z (GMT) No. of bitstreams: 1 cavalca_lb_me_rcla.pdf: 11841916 bytes, checksum: 0d52662f4653c6d3695e6b3ab334549d (MD5) / Made available in DSpace on 2018-04-26T19:16:54Z (GMT). No. of bitstreams: 1 cavalca_lb_me_rcla.pdf: 11841916 bytes, checksum: 0d52662f4653c6d3695e6b3ab334549d (MD5) Previous issue date: 2018-02-26 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A cultura de citros é uma das mais importantes do Brasil, sendo a citricultura brasileira a maior do mundo; ainda assim, a produção nacional sofre com pragas e doenças, como cancro cítrico, que afetam sua produtividade. O cancro cítrico é causado pela bactéria Xanthomonas citri subsp. citri (Xac) e tem sido controlado com o uso de estratégias integradas como a eliminação de plantas contaminadas e pulverização de bactericidas cúpricos. O uso de compostos à base de cobre, porém, representa um risco ambiental devido à sua toxicidade e efeito cumulativo, fazendo necessária a investigação de outros compostos com potencial no tratamento fitossanitário contra a doença. Neste estudo avaliamos a atividade bactericida do galato de hexila contra Xac, seu potencial protetivo e curativo no combate ao cancro cítrico, sua fitotoxicidade e predisposição em induzir resistência bacteriana. O composto provocou retardo e diminuição no crescimento populacional de Xac e inibição de seu crescimento in vitro, levando à morte total da população na concentração de 100μg⋅mL-1. A bactéria não foi capaz de desenvolver resistência a Gal-6 ao longo de 31 dias e exibiu taxa de mutantes naturalmente resistentes ao composto menor que 1⋅10-6 para a concentração de 50μg⋅mL-1. A capacidade de germinação de sementes e desenvolvimento de plântulas de rúcula e tomate não foi alterada por Gal-6. A aspersão de galato de hexila em plantas de laranja doce inoculadas com Xac reduziu em até 35% a incidência de sintomas de cancro cítrico, e em até 80% sua severidade. O composto também alterou o comprimento celular de Xac e permeabilidade de membrana. Galato de hexila mostrou-se um bactericida eficaz contra Xanthomonas citri subsp. citri tanto in vitro quanto in planta, além de apresentar baixa fitotoxicidade e baixa probabilidade de indução de resistência em Xac, visto que o composto parece atuar tanto sobre a estrutura física da membrana, quanto sobre o processo de segregação cromossômica/divisão celular bacteriana. / Citrus culture is one of the most important agricultural activities in Brazil, being the country also the biggest producer in the world; nevertheless, this business struggles with pests and diseases, as citrus canker, that affects its profitability. Citrus canker is caused by the bacterium Xanthomonas citri subsp. citri (Xac) and is controlled by using integrated strategies such as elimination of contaminated plants and spraying of cupric bactericides. Using products with copper, however, brings an environmental risk, given 8 its toxicity and cumulative effect, making necessary the research of other compounds with potential to be used as a resource in the phytosanitary treatment against the disease. We evaluated hexyl galate's (Gal-6) bactericidal activity versus Xac and its potential in the preventive and curative treatments against the disease, also Gal-6 phytotoxicity and likeliness to induce bacterial resistance. The compound caused delay and decrease in Xac population growth and in vitro growth inhibition, leading to the total death of the population when at 100 μg⋅mL-1. The bacterium was not able to develop resistance to Gal-6 over 31 days and exhibited a rate of naturally-resistant mutants to the compound of less than 1⋅10-6 at the concentration of 50μg⋅mL-1. Seed germination and seedling development of arugula and tomato were not altered by Gal- 6. Spraying orange plants infected by Xac with hexyl gallate reduced the incidence of citrus canker symptoms by up to 35% and their severity by up to 80%. The compound also altered Xac cell length and membrane permeability. Hexyl gallate proved to be an effective bactericide against Xanthomonas citri subsp. citri both in vitro and in plant, exhibiting low phytotoxicity and low inclination to induce resistance in Xac, given that the compound appears to act on both the physical structure of the membrane and the process of chromosomal segregation/ bacterial cell division.

Orientador: Francisco de Assis Machado Reis / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-04T13:37:26Z (GMT). No. of bitstreams: 1 Lima_SidneyGoncalode_D.pdf: 16917910 bytes, checksum: 1d80d092bf3733ca0630c99fa60e08b5 (MD5) Previous issue date: 2005 / Doutorado / Quimica Organica / Doutor em Quimica

A new free radical chain process for the allylation of hydrocarbons and some other substrates utilizing substituted allyl bromides (R-H + C=C-C-Br -> R-C-C=C + HBr) has been developed. Good to excellent yields were observed in all cases. Kinetic chain measurements and competition experiments were performed in order to elucidate the mechanism of the reaction. Overall, the results are consistent with a free radical chain process with bromine atom as the chain carrier. Substitution effects on the reactivity of the allyl bromides (CH2=C(Z)CH2Br) and their influence on the overall reaction rate were studied by conducting several competition experiments. The relative rate constants for addition of benzyl radical to CH2=C(Z)CH2Br are: Z=CN(180), COOEt(110), Ph(65), H(1.0). The trend of electronegativity/reactivity of these reactions was very similar to that reported for addition of benzyl radical to substituted alkenes. Other than alkyl aromatics (PhCH3, PhCH(CH3)2), other substrates (i.e., 2- propanol, phenyl cyclopropane) were also tested for this allylation reaction. The magnitude and scope of these reactions, and their synthetic utility is discussed. / Ph. D.

Alkyl derivatives of mercury, especially methylmercury, bring a significant risk to the environment and the human population. Methylmercury is highly toxic compound, which have the potential to bioaccumulate and biomagnify in tissues of aquatic organisms. This diploma thesis deals with issues of alkyl derivatives of mercury in biotic matrices. The goal of this thesis was to analyze fish tissues. Fish were caught from the river Svratka at the inflow and at the outflow of wastewater treatment plant. Methylmercury was determined in fish muscles and skin. Total mercury was determined in fish muscles. The extraction based on acidic digestion in hydrochloric acid and subsequent extraction with toluene was used for isolation of methylmercury from fish tissues. There was used gas chromatography with electron capture microdetector for determination of methylmercury. Total mercury was determined by special analyzer AMA 254.

No description available.

The first step of the synthesis of the hydrocarbon-based chiral surfactant (2) involved the methylation of (S)-leucinol to give (2S)-N-hexadecyl-N,N-dimethyl-(1-hydroxy-4-methyl-1-pentyl)-2-ammonium bromide (2.92g, 67%). The chiral surfactant was synthesized by reacting (2S)-N,N-dimethyl-2-amino-4-methyl-1-pentanol (1) with bromohexadecane (2.06g, 71%). The functionalized styrene for the polymer supported chiral catalyst (6) was synthesized by reacting (1) with 4-vinylbenzyl chloride. The polymerization was carried out with 10% of the functionalized monomer (5) (1.26g, 70.2%), 5% cross-linking agent divinylbenzene, and 85% of styrene with AIBN as the initiator. The structure of each of the products was confirmed by using FTIR and NMR spectroscopy. The activity of the hydrocarbon surfactant and polymeric catalyst were examined by using them as additives in a standard reduction of 2-pentanone with sodium borohydride to yield (R)- and (S)-2-pentanol (3) (4gm, 25%). The resulting alcohol was then esterified with (2S)-methylbutyric acid with iodine as the catalyst and the ester was characterized.

Investigations were performed on the stability, mechanism of formation and an application of alkyl monolayers chemomechanically prepared on silicon surfaces. A new method of surface modification, laser-activation modification of surfaces (LAMS), and multivariate analyses of time-of-flight secondary ion mass spectrometry (ToF-SIMS) images of LAMS spots were also reported. X-ray photoelectron spectroscopy (XPS) and other data show that alkyl monolayers prepared by scribing silicon under 1-iodoalkanes and 1-alkenes were stable over extended periods of time to air, water, a boiling acid and Al Ka X-rays. The stability is attributed to direct Si-C bonding in the monolayers. The observation that the oxygen signals gradually increased and the iodine signals gradually decreased, with both finally reaching plateaus is attributed to the oxidation of exposed silicon by scribing, and the hydrolysis of Si-I bonds, respectively. In alkyl monolayers prepared with 1-alcohols, the carbon signals decreased about 50% after two 1-h immersions in a boiling acid, suggesting unstable Si-O bonding. In the analogous experiment of grinding silicon with alkyl halides, the expected free-radical combination and disproportionation byproducts were observed. This observation provides evidence for the mechanism previously proposed for alkyl monolayer formation on silicon by chemomechanically scribing. Miniaturized sample supports for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) were made on hydrophobic silicon or glass surfaces by scribing. With these sample supports, improved MALDI-MS signal intensities and reproducibilities were achieved for a test peptide, as expected. A new and promising method for surface modification, LAMS, was developed. XPS and ToF-SIMS analyses show that both silicon and germanium were effectively modified by LAMS with even quite inert compounds. This technique was also used to make miniaturized MALDI-MS sample supports. Compared to scribing, LAMS is faster and can be more precisely controlled. Multivariate analyses, automated expert spectral image analysis (AXSIA) and principal component analysis (PCA), were used in interpreting ToF-SIMS images of silicon surfaces modified with 1-alkenes by LAMS. Both analyses show that modified and unmodified areas are chemically different.