This study determines the differences in survival of eight Salmonella strains concentration of BAC in water, followed by regrowth in high and low nutrition conditions containing sublethal concentration of BAC. Our results show strain difference in survival, persistence of Salmonella in BAC at different concentrations. All eight strains of Salmonella were non-recoverable when exposed to 40 to 48 µg/ml BAC for 1h in water. When exposed to 24 µg/ml of BAC for 1 h in water, S. Typhimurium ATCC 14028 and S. Heidelberg ATCC 8326 cells were non-detectable from the initial 7 log CFU/ml. S. Blockley 7175, S. Virchow 7207, S. Poona 01A4242 and S. Poona 00A3208, were non-detectable after 1 h exposure at 24 µg/ml and continued to be non-detectable in 12 µg/ml BAC in both nutrient conditions after 24 h. 3/8 strains formed rugose morphotypes when exposed to BAC thus leading to understanding the role of strain differences.

<p dir="ltr">Water molecules present an obstacle between most synthetic adhesives and surfaces, limiting molecular contact between the glue and substrates. Water can also hydrolyze or swell bulk adhesives, weakening cohesive strength. Nature has solved these challenges for millennia. Marine mussels’ ability to adhere well to wet surfaces stems from an uncommon amino acid, 3,4-dihydroxyphenylalanine (Dopa). The amino acid Dopa contains a catechol moiety that contributes to adhesion and cohesion through hydrogen bonding, metal coordination, and oxidative cross-linking. Hence, biomimetic systems often incorporate catechol groups to provide strong adhesion in both dry and wet environments. In addition to Dopa, mussel adhesive proteins are rich in cationic amino acids lysine and arginine. Previous studies have suggested that cations could displace surface-bound ions, enhancing surface adhesion. However, adhesion performance varied between systems, with no agreement on whether cations are advantageous or disadvantageous. A clear picture of how cations influence underwater adhesion has yet to emerge; therefore, this thesis aims to systematically study these effects.</p><p dir="ltr">In Chapter 2, the synthesis of catechol-containing biomimetic polymers with varying amounts of quaternary ammoniums is presented. Quaternary ammoniums, unlike protonated primary amines, contain non-reactive cations and were used to isolate effects from only charges on adhesion. In Chapter 3, differences between reactive primary amines and quaternary ammoniums were investigated. Structure-function studies have shown how cations influence bulk cohesion versus surface adhesion in dry, under deionized water, and under salt water. The roles of cations in adhesion were complex, with both cohesive and surface bonding relevant in different ways, sometimes even working in opposite directions.</p><p dir="ltr">Furthermore, a styrene-based catechol-containing polymer with excellent underwater adhesion performance is ready to enter the market, but several barriers hinder its industrial implementation. In Chapter 4, new synthetic strategies were developed to scale up and reduce the cost of producing p[vinylcatechol-<i>co-</i>styrene], which are essential for commercialization. This was achieved by selecting cheaper starting materials, switching from anionic to suspension polymerization, and optimizing deprotection reaction conditions. This change also improved adhesion in both dry and underwater conditions. This work is presented as part of our effort to advance the design of adhesives that function in challenging environments.</p>

Mechanisms of adsorption of alkaline copper quat (ACQ) components in wood were investigated with emphasis on: copper chemisorption, copper physisorption, and quat adsorption. Various factors were investigated that could affect the adsorption of individual ACQ components in red pine wood. Copper chemisorption in wood was affected by ligand types coordinating with Cu and the stability of the Cu-ligand complexes in solution. For Cu-monoethanolamine (Cu-Mea) system, the prevailing active solvent species at the solution pH, [Cu(Mea)2-H]+ complexes with wood acid sites and loses one Mea molecule through a ligand exchange reaction. The amount of adsorbed Cu was closely related to the cation exchange capacity of wood. An increase in Mea/Cu ratio increased the proportion of the uncharged Cu-Mea complex and resulted in decreased Cu chemisorption in wood. Copper precipitation is also an important Cu fixation mechanisms of Cu-amine treated wood. X-ray diffraction analysis revealed that in vitro precipitated Cu was a mixture of copper carbonates (azurite and malachite) and possibly Cu2O. Higher concentration Cu-amine solutions retarded the Cu precipitation to a lower pH because of higher free amine in the preservative-wood system. The changes in zeta potential of wood in relationship to the quaternary ammonium (alkyldimethylbenzylammonium chloride: ADBAC) adsorption isotherm showed two different adsorption mechanisms for quat in wood: ion exchange reaction at low concentration and additional aggregation form of adsorption by hydrophobic interaction at high concentration. Because of the aggregation effect, when wood was treated with ACQ, high amounts of ADBAC were concentrated near the surface creating a steep gradient with depth. This aggregated ADBAC was easily leached out while the ion exchanged ADBAC had high leaching resistance. Free Mea and Cu of ACQ components appeared to compete with ADBAC for the same bonding sites in wood.

The effects of ACQ solution parameters such as copper to quat ratio, pH and copper to ligand ratio on distribution of copper complexes in solution and insoluble precipitates, and on fixation and leaching of copper in treated wood were evaluated. The distribution of ionic complexes, predicted by equilibrium speciation model (MINTEQA2), was related to laboratory fixation and leaching results at controlled ACQ solution parameters. A decrease in the relative proportion of copper in the ACQ formulation from a copper oxide (CuO) to didecyldimethylammonium carbonate (DDACb) ratio of 2:1 to 1:1 and 1:2 resulted in lower copper retention in the treated samples and substantially decreased the amount of copper leached per unit area. For monoethanolamine (Mea) based ACQ, solution parameters which favour a higher proportion of monovalent cationic complex, which consume one reactive site in wood, and the presence of insoluble carbonate precipitate of copper in wood during preservative treatment resulted in higher leach resistance compared to the neutral copper complex present at higher pH. Ammonia (NH3) based ACQ can fix more copper at high pH as there is no chelated neutral complex as in Mea based ACQ; however divalent copper-NH3 complexes may consume two sites to fix in wood. Addition of NH3 in Mea based ACQ at Cu:Mea:NH3 ratio of 1:4:6 at pH 10.6 significantly reduced copper leaching compared to 1:4:0 (without ammonia) at pH 9 due to increased divalent copper-ammonia complexes and decreased neutral copper amine complex at elevated pH. Ammonia addition with a lower proportion of Mea (1:2.5:4 at pH 10.5-10.7), significantly reduced copper leaching compared to 1:4:0 at pH 9; no reduction was observed for ammonia addition in ACQ with a higher proportion of Mea (1:4:4 at pH 10.45). The lower copper leaching from 1:2.5:4 resulted from the higher amount of divalent copper-NH3 complexes at higher pH without compromising the amount of copper precipitated at lower pH. The higher percent copper leached from tetramethylethylenediamine (Tmed) based ACQ compared to Mea and NH3 based ACQ suggested that highly stable complexes tend to stay in solution and do not result in leach resistant copper in the wood.

Modelos de Relações Quantitativas entre Estrutura Química e Atividade Biológica (QSAR), previamente gerados no grupo para uma série de brometos de N-benzil-N,N-dimetil-2-(4-X-benzamido)etan-1-amônio substituídos (compostos estruturalmente análogos à procaína), mostraram uma contribuição positiva da lipofilicidade (expressa pelo parâmetro lipofílico, logPapp) para a atividade de bloqueio da transmissão neuromuscular observada para estes. Como os compostos desta série são sais de amônio quaternários, sendo alguns altamente hidrofílicos, as determinações dos seus valores de logPapp pelo método shake-flask acarretam dificuldades experimentais, levando a altas incertezas. Para contornar estas dificuldades, em outro trabalho iniciado no grupo, sugeriu-se, como estratégia metodológica, avaliar a aplicação do conceito do par iônico, usando, para tanto, um contraíon grande e hidrofóbico. Assim, observou-se, para um único composto desta série, o aumento da sua lipofilicidade, por possível formação de par iônico, tornando-o menos hidrofílico. Nesta dissertação, visando ampliar os estudos envolvendo a aplicação desta estratégia metodológica e seus efeitos sobre a lipofilicidade, outros compostos foram selecionados para que uma faixa mais ampla de valores de LogPapp pudesse ser avaliada. Para tanto, os valores de logPapp de cinco compostos desta série foram determinados pelo método shake-flask, usando o sistema n-octanol/água, avaliando-se, ainda, os efeitos da força iônica na partição. Para estes, a faixa de valores de LogPapp determinados variou de -1,73 a 0,99. Para avaliar a aplicação do conceito do par iônico como estratégia, os valores de LogPapp destes compostos foram determinados na presença de diferentes concentrações do contraíon hidrofóbico n-octil sulfato de sódio (OcS). Verificou-se aumento da lipofilicidade com aumento das concentrações de OcS. Obteve-se, também, os correspondentes valores de LogPapp extrapolados para concentração zero de OcS (LogPapp0), que concordaram, dentro do erro experimental, com os valores determinados diretamente na ausência de OcS. Estes resultados indicam que o conceito do par iônico pode ser aplicado como estratégia metodológica, para melhorar as condições experimentais e diminuir as incertezas nas determinações de valores de LogPapp para esta série de brometos de amônio quaternários hidrofílicos. Finalmente, foram realizados experimentos complementares para verificar a formação de par iônico: (i) determinações dos valores de logP da benzamida (composto sem carga permanente) na presença de OcS; (ii) análise por RMN de um dos compostos desta série, na presença de OcS. Ambos indicaram que, somente para os brometos de amônio quaternários estudados, o aumento da lipofilicidade observado ocorre por possível formação de par iônico. E, ainda, foi avaliada a aplicação do conceito do par iônico e seus efeitos sobre a lipofilicidade do QX-222 e do brometo de neostigmina (compostos altamente hidrofílicos), revelando limitações na sua aplicação como estratégia metodológica. / Quantitative Structure-Activity Relationships (QSAR) models previously generated in our group for a set of N-benzyl-N,N-dimethyl-2-(4-X-benzamido)ethan-1-ammonium bromides (procaine structural analogs) showed a positive contribution of the lipophilic term (expressed by the partition coefficient, logPapp) to their neuromuscular blockage activity. However, since some of them are hydrophilic quaternary ammonium bromides, their logPapp measurements were usually associated with experimental shortcomings, leading to low accuracy logPapp values. In order to make these experiments more feasible, the application of the ion-pair concept was evaluated as a methodological strategy in another previous work, initially to one compound of this set. For this purpose, logPapp measurements have been done in the presence of a large and hydrophobic counter ion, leading to an increase of its lipophilicity, due to possible ion-pair formation. In the present work, in order to further investigate this strategy and its effects on the lipophilicity, we include more compounds, allowing the assessment of a wider range of logPapp values. Thus, logPapp values of five compounds were obtained by the shake-flask method, using n-octanol/water, with and without ionic strength adjustment. For them, logPapp range values were determined from -1.73 to 0.99. To evaluate the application of the ion-pair concept as strategy, logPapp values of these compounds were determined in the presence of eleven sodium octyl sulfate (OcS) concentrations. It was observed that the lipophilicity of these compounds, increased with the addition of OcS. Moreover, we obtained the corresponding logPapp values extrapolated to zero OcS concentration (logPapp0), which agreed, within the experimental error, with the corresponding values determined in absence of OcS. These results suggest that the ion-pair concept can be applied as a strategy to improve the experimental conditions, increasing the accuracy of logPapp measurements for this set of hydrophilic quaternary ammonium bromides. Finally, supplementary experiments were done to verify the ion-pair formation: (i) measurement of logP values of benzamide (not a permanent ion) in presence of OcS; (ii) NMR spectroscopy analysis of one compound of this set, also in presence of OcS. Both indicated that only for the studied quaternary ammonium bromides the lipophilicity increase is due to possible ion-pair formation. Additionally, the application of the ion-pair concept and its effects on the lipophilicity was evaluated for QX-222 and for neostigmine bromide (highly hydrophilic compounds), which revealed limitations in its application as a methodological strateg

A resina acrílica para base de próteses removíveis é capaz de acumular biofilme e assim favorecer o aparecimento de diversos problemas na cavidade bucal dos usuários de próteses. A imobilização de um agente antisséptico na matriz polimérica tem potencial preventivo frente a esse acúmulo, mas necessita de maior investigação. O objetivo deste estudo foi avaliar as propriedades biológicas do brometo de metacriloiloxiundecilpiridínio (MUPB), um composto antisséptico capaz de copolimerizar-se com as resinas acrílicas. Foram determinadas as concentrações inibitória e fungicida/bactericida mínimas (CIM, CFM/CBM) do MUPB frente às espécies Candida albicans, Candida dubliniensis, Candida glabrata, Lactobacillus casei, Staphylococcus aureus e Streptococcus mutans, em comparação ao cloreto de cetilpiridínio (CCP). A seguir, investigou-se a citotoxicidade do MUPB em fibroblastos, comparando-o com o metil metacrilato (MMA). A avaliação da atividade antimicrobiana de diferentes concentrações do MUPB em massa (0, 0,3% e 0,6%) incorporado em uma resina acrílica termopolimerizável para base de próteses foi realizada por meio de testes de difusão em disco e quantificação de unidades formadoras de colônia (UFC) aderidas à resina após contato com suspensões de cada micro-organismo. A adesão microbiana também foi avaliada por microscopia eletrônica de varredura. Comparações entre o MUPB e as demais substâncias, bem como entre as concentrações incorporadas na resina, foram realizadas com &alpha;=0,05. O MUPB apresentou CIM inferior ao CCP para C. dublinienses e S. mutans (P=0,046 e 0,043, respectivamente). Para as demais espécies, as diferenças não foram significantes. Para a CFM/CBM, só foi encontrada diferença significante para C. albicans (P=0,046). O MUPB não polimerizado mostrou-se em torno de 20 vezes mais citotóxico que o MMA. Independente da concentração incorporada e da espécie, não houve formação de halo de inibição em torno dos espécimes. A incorporação do MUPB só influenciou na adesão de C. albicans (P=0,003), com menores contagens de UFC para o grupo com 0,6%. Conclui-se que o MUPB não polimerizado tem capacidade antimicrobiana próxima à do CCP, e alta citotoxicidade, se comparado ao MMA. A atividade antimicrobiana, após incorporação em uma resina acrílica para base de prótese, não depende de sua eluição, porém apresentou-se restrita à C. albicans. / Acrylic resins for removable denture base are capable of accumulating biofilm and thus favor the appearance of various problems in the edentulous oral cavity. An antiseptic agent immobilized within the polymeric matrix has a preventive potential against this accumulation, but requires further investigation. The aim of this study was to evaluate the biological properties of methacryloyloxyundecylpyridinium bromide (MUPB), an antiseptic monomer capable of copolymerizing with acrylic resins. The minimum inhibitory and fungicidal/bactericidal concentrations (MIC, MFC/MBC) of MUPB were determined against the species Candida albicans, Candida dubliniensis, Candida glabrata, Lactobacillus casei, Staphylococcus aureus and Streptococcus mutans, in comparison with cetylpyridinium chloride (CCP). After this, the cytotoxicity of MUPB was investigated in fibroblasts, compared with methyl methacrylate (MMA). The antimicrobial activity of different concentrations of MUPB (0, 0.3% and 0.6% w/w) incorporated into a heat polymerized denture base acrylic resin was evaluated by means of disk diffusion tests, and the CFUs adhered to the resin after contact with suspensions of each microorganism were quantified. Microbial adhesion was also evaluated by scanning electron microscopy. Comparisons were made between MUPB and the other substances, as well as between the concentrations incorporated into the resin (&alpha;=.05). MUPB presented a lower MIC than CCP for C. dubliniensis and S. mutans (P=.046 and .043, respectively). For the other species, the differences were not significant. For MFC or MBC, significant difference was found only for C. albicans (P=.046). Non polymerized MUPB was shown to be 20 times more cytotoxic than MMA. Irrespective of the concentration incorporated and the species, there was no growth of inhibition halo around the specimens. The incorporation of MUPB only influenced the adhesion of C. albicans (P=.003), with lower CFU counts for the group with the concentration of 0.6%. It was concluded that non polymerized MUPB has an antimicrobial capacity close to that of CCP, and high cytotoxicity when compared with MMA. The antimicrobial activity after incorporation within a denture base acrylic resin did not depend on its elution, but was shown to be restricted to C. albicans.

A resina acrílica para base de próteses removíveis é capaz de acumular biofilme e assim favorecer o aparecimento de diversos problemas na cavidade bucal dos usuários de próteses. A imobilização de um agente antisséptico na matriz polimérica tem potencial preventivo frente a esse acúmulo, mas necessita de maior investigação. O objetivo deste estudo foi avaliar as propriedades biológicas do brometo de metacriloiloxiundecilpiridínio (MUPB), um composto antisséptico capaz de copolimerizar-se com as resinas acrílicas. Foram determinadas as concentrações inibitória e fungicida/bactericida mínimas (CIM, CFM/CBM) do MUPB frente às espécies Candida albicans, Candida dubliniensis, Candida glabrata, Lactobacillus casei, Staphylococcus aureus e Streptococcus mutans, em comparação ao cloreto de cetilpiridínio (CCP). A seguir, investigou-se a citotoxicidade do MUPB em fibroblastos, comparando-o com o metil metacrilato (MMA). A avaliação da atividade antimicrobiana de diferentes concentrações do MUPB em massa (0, 0,3% e 0,6%) incorporado em uma resina acrílica termopolimerizável para base de próteses foi realizada por meio de testes de difusão em disco e quantificação de unidades formadoras de colônia (UFC) aderidas à resina após contato com suspensões de cada micro-organismo. A adesão microbiana também foi avaliada por microscopia eletrônica de varredura. Comparações entre o MUPB e as demais substâncias, bem como entre as concentrações incorporadas na resina, foram realizadas com &alpha;=0,05. O MUPB apresentou CIM inferior ao CCP para C. dublinienses e S. mutans (P=0,046 e 0,043, respectivamente). Para as demais espécies, as diferenças não foram significantes. Para a CFM/CBM, só foi encontrada diferença significante para C. albicans (P=0,046). O MUPB não polimerizado mostrou-se em torno de 20 vezes mais citotóxico que o MMA. Independente da concentração incorporada e da espécie, não houve formação de halo de inibição em torno dos espécimes. A incorporação do MUPB só influenciou na adesão de C. albicans (P=0,003), com menores contagens de UFC para o grupo com 0,6%. Conclui-se que o MUPB não polimerizado tem capacidade antimicrobiana próxima à do CCP, e alta citotoxicidade, se comparado ao MMA. A atividade antimicrobiana, após incorporação em uma resina acrílica para base de prótese, não depende de sua eluição, porém apresentou-se restrita à C. albicans. / Acrylic resins for removable denture base are capable of accumulating biofilm and thus favor the appearance of various problems in the edentulous oral cavity. An antiseptic agent immobilized within the polymeric matrix has a preventive potential against this accumulation, but requires further investigation. The aim of this study was to evaluate the biological properties of methacryloyloxyundecylpyridinium bromide (MUPB), an antiseptic monomer capable of copolymerizing with acrylic resins. The minimum inhibitory and fungicidal/bactericidal concentrations (MIC, MFC/MBC) of MUPB were determined against the species Candida albicans, Candida dubliniensis, Candida glabrata, Lactobacillus casei, Staphylococcus aureus and Streptococcus mutans, in comparison with cetylpyridinium chloride (CCP). After this, the cytotoxicity of MUPB was investigated in fibroblasts, compared with methyl methacrylate (MMA). The antimicrobial activity of different concentrations of MUPB (0, 0.3% and 0.6% w/w) incorporated into a heat polymerized denture base acrylic resin was evaluated by means of disk diffusion tests, and the CFUs adhered to the resin after contact with suspensions of each microorganism were quantified. Microbial adhesion was also evaluated by scanning electron microscopy. Comparisons were made between MUPB and the other substances, as well as between the concentrations incorporated into the resin (&alpha;=.05). MUPB presented a lower MIC than CCP for C. dubliniensis and S. mutans (P=.046 and .043, respectively). For the other species, the differences were not significant. For MFC or MBC, significant difference was found only for C. albicans (P=.046). Non polymerized MUPB was shown to be 20 times more cytotoxic than MMA. Irrespective of the concentration incorporated and the species, there was no growth of inhibition halo around the specimens. The incorporation of MUPB only influenced the adhesion of C. albicans (P=.003), with lower CFU counts for the group with the concentration of 0.6%. It was concluded that non polymerized MUPB has an antimicrobial capacity close to that of CCP, and high cytotoxicity when compared with MMA. The antimicrobial activity after incorporation within a denture base acrylic resin did not depend on its elution, but was shown to be restricted to C. albicans.

Modelos de Relações Quantitativas entre Estrutura Química e Atividade Biológica (QSAR), previamente gerados no grupo para uma série de brometos de N-benzil-N,N-dimetil-2-(4-X-benzamido)etan-1-amônio substituídos (compostos estruturalmente análogos à procaína), mostraram uma contribuição positiva da lipofilicidade (expressa pelo parâmetro lipofílico, logPapp) para a atividade de bloqueio da transmissão neuromuscular observada para estes. Como os compostos desta série são sais de amônio quaternários, sendo alguns altamente hidrofílicos, as determinações dos seus valores de logPapp pelo método shake-flask acarretam dificuldades experimentais, levando a altas incertezas. Para contornar estas dificuldades, em outro trabalho iniciado no grupo, sugeriu-se, como estratégia metodológica, avaliar a aplicação do conceito do par iônico, usando, para tanto, um contraíon grande e hidrofóbico. Assim, observou-se, para um único composto desta série, o aumento da sua lipofilicidade, por possível formação de par iônico, tornando-o menos hidrofílico. Nesta dissertação, visando ampliar os estudos envolvendo a aplicação desta estratégia metodológica e seus efeitos sobre a lipofilicidade, outros compostos foram selecionados para que uma faixa mais ampla de valores de LogPapp pudesse ser avaliada. Para tanto, os valores de logPapp de cinco compostos desta série foram determinados pelo método shake-flask, usando o sistema n-octanol/água, avaliando-se, ainda, os efeitos da força iônica na partição. Para estes, a faixa de valores de LogPapp determinados variou de -1,73 a 0,99. Para avaliar a aplicação do conceito do par iônico como estratégia, os valores de LogPapp destes compostos foram determinados na presença de diferentes concentrações do contraíon hidrofóbico n-octil sulfato de sódio (OcS). Verificou-se aumento da lipofilicidade com aumento das concentrações de OcS. Obteve-se, também, os correspondentes valores de LogPapp extrapolados para concentração zero de OcS (LogPapp0), que concordaram, dentro do erro experimental, com os valores determinados diretamente na ausência de OcS. Estes resultados indicam que o conceito do par iônico pode ser aplicado como estratégia metodológica, para melhorar as condições experimentais e diminuir as incertezas nas determinações de valores de LogPapp para esta série de brometos de amônio quaternários hidrofílicos. Finalmente, foram realizados experimentos complementares para verificar a formação de par iônico: (i) determinações dos valores de logP da benzamida (composto sem carga permanente) na presença de OcS; (ii) análise por RMN de um dos compostos desta série, na presença de OcS. Ambos indicaram que, somente para os brometos de amônio quaternários estudados, o aumento da lipofilicidade observado ocorre por possível formação de par iônico. E, ainda, foi avaliada a aplicação do conceito do par iônico e seus efeitos sobre a lipofilicidade do QX-222 e do brometo de neostigmina (compostos altamente hidrofílicos), revelando limitações na sua aplicação como estratégia metodológica. / Quantitative Structure-Activity Relationships (QSAR) models previously generated in our group for a set of N-benzyl-N,N-dimethyl-2-(4-X-benzamido)ethan-1-ammonium bromides (procaine structural analogs) showed a positive contribution of the lipophilic term (expressed by the partition coefficient, logPapp) to their neuromuscular blockage activity. However, since some of them are hydrophilic quaternary ammonium bromides, their logPapp measurements were usually associated with experimental shortcomings, leading to low accuracy logPapp values. In order to make these experiments more feasible, the application of the ion-pair concept was evaluated as a methodological strategy in another previous work, initially to one compound of this set. For this purpose, logPapp measurements have been done in the presence of a large and hydrophobic counter ion, leading to an increase of its lipophilicity, due to possible ion-pair formation. In the present work, in order to further investigate this strategy and its effects on the lipophilicity, we include more compounds, allowing the assessment of a wider range of logPapp values. Thus, logPapp values of five compounds were obtained by the shake-flask method, using n-octanol/water, with and without ionic strength adjustment. For them, logPapp range values were determined from -1.73 to 0.99. To evaluate the application of the ion-pair concept as strategy, logPapp values of these compounds were determined in the presence of eleven sodium octyl sulfate (OcS) concentrations. It was observed that the lipophilicity of these compounds, increased with the addition of OcS. Moreover, we obtained the corresponding logPapp values extrapolated to zero OcS concentration (logPapp0), which agreed, within the experimental error, with the corresponding values determined in absence of OcS. These results suggest that the ion-pair concept can be applied as a strategy to improve the experimental conditions, increasing the accuracy of logPapp measurements for this set of hydrophilic quaternary ammonium bromides. Finally, supplementary experiments were done to verify the ion-pair formation: (i) measurement of logP values of benzamide (not a permanent ion) in presence of OcS; (ii) NMR spectroscopy analysis of one compound of this set, also in presence of OcS. Both indicated that only for the studied quaternary ammonium bromides the lipophilicity increase is due to possible ion-pair formation. Additionally, the application of the ion-pair concept and its effects on the lipophilicity was evaluated for QX-222 and for neostigmine bromide (highly hydrophilic compounds), which revealed limitations in its application as a methodological strateg

Para aumentar os volumes de extração de petróleo, resolver e prevenir problemas nas operações de produção são utilizados diversos produtos químicos, dentre os quais se destacam os inibidores de corrosão, que são utilizados em toda cadeia produtiva do petróleo visando proteger o sistema da deterioração por corrosão. Os sais de amônio quaternário são uma das classes de inibidores mais utilizadas pela indústria do petróleo devido a sua grande eficiência. Entretanto, sua solubilidade em água faz com que estejam presentes na água produzida representando um risco para contaminação ambiental, visto que possuem baixa biodegrabilidade e potencial de bioacumulação. Como se encontram misturados a outros produtos químicos e sob efeitos das variações do ambiente em que são aplicados, definir um método de análise confiável e viável para monitoramento em linha representa um desafio para os laboratórios de campos de produção. Neste trabalho, foi estudado o emprego da fluorescência de ultravioleta na quantificação de um inibidor de corrosão do tipo sal de amônio quaternário em água. Foram obtidos espectros de emissão do produto comercial em água, além do estudo de variáveis instrumentais e interferentes presentes na água produzida. A comparação com padrões de sal de amônio quaternário permitiu identificar como principal fluorófilo, um sal alquil-aril de amônio quaternário. Estudos de estabilidade revelaram que a adsorção do inibidor de corrosão nas superfícies dos frascos plásticos provoca a queda do sinal fluorescente e que a adição de isopropanol reduz este efeito de 40 para 24%. Foram obtidas curvas de calibração com a formulação comercial e com o cloreto de 2-metil-4-dodecil-benzil-trimetil amônio com uma boa correlação. Amostras sintéticas do inibidor foram determinadas com um erro relativo de 2,70 a 13,32%. O método de adição padrão foi avaliado usando uma amostra de água produzida, e os resultados não foram satisfatórios, devido à interferência, principalmente, de compostos orgânicos aromáticos presentes / In order to increase the volume of oil extraction, solve and prevent problems in oil production, several chemical products are used. Corrosion inhibitors are the main chemical products used in the whole oil production chain, whose objective is to protect the system from deterioration caused by corrosion. The quaternary ammonium salts are the kind of inhibitor which is more frequently used by the oil industry due to its great efficiency. However, its solubility in water allows them to remain in the produced water representing a risk of environmental contamination, since they have low biodegrability and tendency to bioaccumulation. Once they are mixed to other chemical products and affected by the variations of the environment where they are applied, it becomes a challenge to production field laboratories to select a reliable and viable analysis method for on-line monitoring. This essay tends to focus on the use of the ultraviolet fluorescence in the quantification of an inhibitor of corrosion of the quaternary ammonium salt type in water. There has been obtained emission spectra of the commercial product in water besides the study of instrumental variables and interference of chemical substances in the produced water. The comparison with quaternary ammonium salt standards allow identifying an alkyl-aryl quaternary ammonium salt as the main fluorophore. Tests of stability have demonstrated that the addition of isopropyl alcohol reduces the fall of the fluorescent signal from 40 to 24% in three days time. This fall is caused by the adsorption of corrosion inhibitor in the surface of plastic containers. Good correlation curves of calibration have been obtained with commercial formularization and methyldodecylbenzyl trimethyl ammonium chloride. Synthetic samples of inhibitor have been determined with a relative error from 2,70 to 13,32%. One produced water sample from a production field has been used to evaluate the standard addition method. Satisfactory results have not been successfully achieved, principally, due to the interference of aromatics organic compounds found in the water sample

Le chondrosarcome (CHS), cancer du cartilage est une tumeur chimio- et radiorésistance dont le seul traitement efficace reste la chirurgie. Une prodrogue vectorisée et activable en hypoxie, ICF05016, est actuellement développée par l’UMR 1240, et évaluée en préclinique comme potentielle alternative théra-peutique pour ce cancer. La structure de cette molécule regroupe i) une moutarde cytotoxique, ii) un vecteur ammonium quaternaire chargé positivement possédant un tropisme pour l’aggrécane, protéoglycane majoritaire de la matrice extracellulaire tumorale, iii) une gâchette de type 2-nitroimidazole permettant une activation sélective en situation d’hypoxie, une des caractéristiques principales du CHS.Ces travaux de thèse ont consisté à pharmaco-moduler cette prodrogue bispécifique ICF05016 en modifiant la position du vecteur ainsi que la nature de l’agent cytotoxique. Ainsi sept prodrogues vectorisées ont été synthétisées présentant une chaine vectrice N,N,N-triméthylpropylaminium soit en C-4, soit en N-1 du cycle imidazole. Leur activation par réduction chimique, mimant l’hypoxie, ainsi que leur affinité pour l’aggrécane ont été confirmées in tubo par des analyses de RMN 31P et de SPR, toutefois elles se sont avérées non sélectives en termes de cytotoxicité (CI50 comprises entre 15 et 1 µM, et ce, quelles que soient les conditions d’oxygénation) et faiblement sensibles à une bio-réduction enzymatique. La fonctionnalisation par un vecteur ammonium quaternaire de la gâchette 2-nitroimidazole annihile donc l’activation en hypoxie des prodrogues.Cette stratégie a ensuite été étendue au cancer de la prostate en remplaçant le vecteur ammonium quaternaire par un ligand de type urée affin pour l’antigène membranaire spécifique de la prostate (PSMA). La première molécule synthétisée, qui possède un espaceur triazole, a démontré une affinité pour le récepteur PSMA, par une étude de compétition avec un radioligand, ainsi qu’une activation in tubo par bioréduction enzymatique. Toutefois aucune cytotoxicité n’a été constatée sur les lignées LNCaP-Luc et PC3-Luc. Une seconde molécule combinant un espaceur triazole avec une séquence peptidique identifiée pour la molécule PSMA-617, actuellement en cours d’essai clinique, est actuellement développée mais sa synthèse doit être optimisée, notamment au niveau de l’étape de cycloaddition 1,3-dipolaire. / Chondrosarcoma (CHS), the malignant tumor of the cartilage, is a chemo- and radio-resistant cancer. Surgical resection is still considered the mainstay of treatment of this pathology. A dual targeted hypoxia-activated prodrug, ICF05016 was developed by the UMR 1240 and evaluated in preclinical studies as a potential therapeutic alternative for CHS. The latter is a nitroheteroaryl-based compound designed as follows: a phosphorodiamidic mustard functionalized with a quaternary ammonium (QA) used as targeting function, and a 2-nitroimidazole group to trigger fragmentation and then release the bis-alkylating mustard anion by bioreduction under hypoxic conditions, chemical hallmark of CHS.This project deals with the pharmacomodulation of ICF05016, more specifically by modification of the position of the targeting moiety as well as the nature of the cytotoxic agent. Seven QA-targeted prodrugs have been synthesized with N,N,N-trimethylpropylaminium tethered to the imidazole either in the C-4, or the N-1 position. These prodrugs were cleaved in vitro under chemical reductive conditions, which mimic in vivo hypoxia conditions. In addition, the binding of these derivatives to aggrecan was highlighted by surface plasmon resonance. In vitro assays on human CHS cells (H-EMC-SS) demonstrated quite equivalent cytotoxicities, whatever the oxygen conditions used and their evaluation as substrate of an oxygen-insensitive nitroreductase revealed the almost total lack of activation. A QA targeting moiety grafted on the trigger seems to alter hypoxia activation.New prodrugs with prostate specific membrane antigen (PSMA)-targeting ligand were synthesized to extend this HAP strategy to prostate cancer. The first tested compound, having a triazole spacer, presented selective affinity for PSMA in an in vitro binding experiment as well as activation under enzymatic reduction. However, no cytotoxicity was observed on LNCaP-Luc and PC3-Luc cells. The synthesis of a prodrug combining the spacer of PSMA-617, currently in clinical trial, and a propyltriazole moiety, was initiated but the 1,3-dipolar cycloaddition still need to be optimized.