The Swedish   healthcare system today has longer queues than before, low treatment rates   and lack of accessibility, treatment and service. Business Intelligence   System (BIS) purpose is to support organizations and businesses in different   types of decision-making that in turn can make the operations more efficient.   The purpose of this thesis is to develop and test a model that describes the   effects that BIS have on the healthcare system according to previous research   on Swedish healthcare staff and their experiences of these systems. The study   has been carried out through qualitative interviews with respondents who work   with BIS in the Swedish healthcare system. A model developed from previous   research has according to the purpose of this study been developed and tested   against the collected empirical data to see if the effects that the previous   research has identified are in line with what Swedish healthcare staff has identified.   The entire model which consists of BIS basic functionality and BIS effects on   healthcare has been tested against another respondent who did not participate   on any interview but instead performed a thorough analysis of the whole   model. What were tested by this respondent were the model’s flow, structure   and constituents. The result of this study came to the conclusion that the   basic functionality of the model developed and the identified effects are in   accordance with the effects identified by the Swedish healthcare staff they   receive from the BIS within their work. / Sammanfattning: Den svenska sjukvården har idag längre köer än   tidigare, låg behandlingstakt och brister i tillgänglighet, bemötande och   service. Business Intelligence System (BIS) har som syfte att stödja   organisationer och verksamheter vid olika typer av beslutstaganden som i sin   tur kan effektivisera verksamheten. Syftet med detta examensarbete är att   utveckla och testa en modell som beskriver de effekter som BIS har på   sjukvården enligt tidigare forskning mot svensk sjukvårdspersonal och deras   upplevelser utav dessa system. Studien har utförts genom kvalitativa   intervjuer med respondenter som arbetar med BIS inom den svenska sjukvården.   En modell som bygger på tidigare forskning har enligt syftet i denna studie   utvecklats och testats mot den insamlade empirin för att se om de effekter   som den tidigare forskningen har identifierat stämmer överens med vad svensk   sjukvårdspersonal har identifierat. Hela modellen som består av BIS   grundläggande funktionalitet samt BIS effekter på sjukvården har sedan   testats mot ytterligare en respondent som inte deltog i någon intervju utan   endast analyserat modellens helhet. Det som testades av denna respondent var   modellens flöde, struktur och beståndsdelar. Resultatet av denna studie kom   fram till att den framtagna modellens grundläggande funktionalitet samt de   effekter som återfinns i modellen stämmer överens med de effekter som den   svenska sjukvårdspersonalen har identifierat att de får ut av BIS inom sitt   arbete.,

Neste trabalho foram realizadas as sínteses dos complexos [Ru(NH3)5(t-bpe)](PF6)2, [Ru(NH3)5(t-bpe)](PF6)3, trans-[Ru(SO4)(NH3)4(t-bpe)]Cl•nH2O, trans-[Ru(NH3)4(H2O)(t-bpeH)](PF6)3, trans-[Ru(NH3)4(H2O)(t-bpe)](PF6)3, trans-[Ru(SO4)(4-acpy)(NH3)4]Cl•nH2O, trans-[Ru(NH3)4(H2O)(4-acpy)](PF6)2, trans-[Ru(4-acpy)(NH3)4(t-bpe)](PF6)2, trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O, [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(SO4)(NH3)4](PF6)5•nH2O e [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O. Os compostos foram analisados e caracterizados por espectroscopia na região do UV-visível e do infravermelho, espectroscopia de ressonância magnética nuclear, análise elementar e técnicas eletroquímicas. O espectro de absorção na região do infravermelho mostrou para o composto trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O uma banda em 1935 cm-1 e para o [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O uma banda em 1925 cm-1. Estas bandas foram atribuídas à freqüência de estiramento NO indicando a coordenação deste ao centro metálico e que este possui um caráter de nitrosônio. Os espectros eletrônicos dos complexos [Ru(NH3)5(t-bpe)](PF6)2, trans-[Ru(NH3)4(H2O)(t-bpeH)](PF6)3, trans-[Ru(NH3)4(H2O)(4-acpy)](PF6)2 e trans-[Ru(4-acpy)(NH3)4(t-bpe)](PF6)2 apresentaram, na região do visível, bandas de transição de transferência de carga metal-ligante (TCML) e, na região do ultravioleta, bandas de transição interna do ligante (IL). Os compostos [Ru(NH3)5(t-bpe)](PF6)3, trans-[Ru(SO4)(NH3)4(t-bpe)]Cl•nH2O, trans-[Ru(SO4)(4-acpy)(NH3)4]Cl•nH2O, trans-[Ru(NH3)4(H2O)(t-bpe)](PF6)3 e [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(SO4)(NH3)4](PF6)5•nH2O apresentaram, na região de 300 a 400 nm, bandas de transição de transferência de carga ligante-metal (TCLM) e, abaixo de 300 nm, bandas de transição interna do ligante (IL). Os espectros dos complexos trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O e [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O apresentaram bandas na região de 320 nm com absortividades molares de, aproximadamente, 2,8.10-4 L mol-1 cm-1, atribuídas a uma mistura de transições, sendo elas: campo ligante (CL), transferência de carga ligante-ligante (TCLL), interna do ligante (IL) e transferência de carga metal-ligante (TCML). Os valores de pKas referentes à desprotonação do t-bpe nos compostos [RuII(NH3)5(t-bpeH)]3+ (pKa 5,1), [RuIII(NH3)5(t-bpeH)]4+ (pKa 3,6), trans-[RuII(NH3)5(H2O)(t-bpeH)]3+ (pKa 4,5), trans-[RuIII(NH3)4(H2O)(t-bpeH)]4+ (pKa 2,8) e trans-[Ru(NO)(NH3)4(t-bpeH)]4+ (pKa 2,3) foram determinados e pode-se perceber a influência do estado de oxidação do rutênio no pKa destes compostos. Nos complexos [RuIII(NH3)5(t-bpeH)]4+ e trans-[RuIII(NH3)5(H2O)(t-bpeH)]4+, que apresentam o rutênio no estado de oxidação (III), os pKas determinados foram menores do que os dos complexos com o rutênio no estado de oxidação (II) ([RuII(NH3)5(t-bpeH)]3+ e trans-[RuII(NH3)5(H2O)(t-bpeH)]3+). Já no complexo trans-[Ru(NO)(NH3)4(t-bpeH)]4+ o pKa foi menor do que todos eles, indicando que o rutênio neste complexo se assemelha a um Ru(III). O espectro de ressonância magnética nuclear de hidrogênio do composto [Ru(NH3)5(t-bpe)](PF6)2 apresentou 3 sinais, de 8,6 a 7,6 ppm, com integração de 4:4:2, referente aos hidrogênios aromáticos e etilênicos do ligante t-bpe. Para o trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O 5 sinais na região de 8,7 e 7,6 ppm são observados devido à influência do NO, sendo que um deles é um duplo dubleto referente aos hidrogênios etilênicos. O espectro do [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O, apresentou 6 sinais na região de 8,8 e 7,2 ppm, com integração de 2:2:4:2:2:2 referentes aos hidrogênios aromáticos e etilênicos do t-bpe e aromáticos do 4-acpy. Apenas processos de oxidação/redução Ru2+/3+ foram verificados nos voltamogramas cíclicos dos complexos [Ru(NH3)5(t-bpe)](PF6)2 (E1/2’ = +116 mV vs Ag/AgCl), trans-[Ru(NH3)4(H2O)(t-bpeH)](PF6)3 (E1/2’ = +165 mV vs Ag/AgCl), trans-[Ru(4-acpy)(NH3)4(H2O)](PF6)2 (E1/2’ = +247 mV vs Ag/AgCl) e trans-[Ru(4-acpy)(NH3)4(t-bpe)](PF6)2 (E1/2’ = +405 mV vs Ag/AgCl). Nos trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O e [trans-Ru(4-acpy)(NH3)4(-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O foram observados processos {RuNO}3+/{RuNO}2+ (Ec = -170 mV vs Ag/AgCl e Ec = -188 mV vs Ag/AgCl, respectivamente) além de picos catódicos que indicam processos {RuNO}2+/{RuNO}+ (Ec = -640 mV vs Ag/AgCl e Ec = -650 mV vs Ag/AgCl, respectivamente). O composto trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O foi irradiado em 313 e em 366 nm em pHs 1,2 e 7,0. Estas irradiações foram acompanhadas por espectroscopia de absorção na região do Uv-visível e o aumento da banda em 374 nm indicou a formação do complexo trans-[Ru(NH3)4(H2O)(t-bpe)]3+. Além disso, a liberação de NO foi acompanhada por espectroscopia na região do infravermelho, ocorrendo a diminuição da banda de estiramento NO do complexo trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O, confirmando a saída de NO. Os rendimentos quânticos para a saída de NO do complexo para irradiações em 313 nm em pH 1,2 e 7,0 (0,10 e 0,12, respectivamente) e em 366nm em pH 1,2 e 7,0 (0,04 e 0,04, respectivamente) estão próximos aos de outros trans-[Ru(NO)(NH3)4(L)]3+ em que L é um derivado piridínico. Testes fotoquímicos preliminares foram realizados com o complexo [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O mostrando-se bastante promissores, visto que além da liberação de NO quando a irradiação é feita com luz ultravioleta, ela também ocorre com luz visível. Os dados obtidos mostraram uma fraca comunicação eletrônica entre as extremidades do t-bpe e que a liberação de NO com irradiação com luz visível no [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O é fruto desta fraca comunicação que faz com que o complexo binuclear absorva no visível. Isto torna essa classe de complexos bastante promissora para o desenvolvimento de doadores de NO para aplicações biológicas, como terapia fotodinâmica. / In this work, the synthesis of the complexes [Ru(NH3)5(t-bpe)](PF6)2, [Ru(NH3)5(t-bpe)](PF6)3, trans-[Ru(SO4)(NH3)4(t-bpe)]Cl•nH2O, trans-[Ru(NH3)4(H2O)(t-bpeH)](PF6)3, trans-[Ru(NH3)4(H2O)(t-bpe)](PF6)3, trans-[Ru(SO4)(4-acpy)(NH3)4]Cl•nH2O, trans-[Ru(NH3)4(H2O)(4-acpy)](PF6)2, trans-[Ru(4-acpy)(NH3)4(t-bpe)](PF6)2, trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O, [trans-Ru(4-acpy)(NH3)4(t-bpe)trans-Ru(SO4)(NH3)4](PF6)5•nH2O and [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O are reported. The compounds were analyzed and characterized by UV-visible and IR spectroscopy, NMR, elemental analysis and electrochemical techniques. The infrared spectra of trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O showed an absorption band at 1935 cm-1 and that of [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O a band at 1925 cm-1. These bands were assigned to the stretching frequency of NO indicating its coordination to the metallic center, and a nitrosonium character. In the electronic spectra of the [Ru(NH3)5(t-bpe)](PF6)2, trans-[Ru(NH3)4(H2O)(t-bpeH)](PF6)3, trans-[Ru(NH3)4(H2O)(4-acpy)](PF6)2 and trans-[Ru(4-acpy)(NH3)4(t-bpe)](PF6)2 a metal-ligand charge transfer (MLCT) transition, in the visible region, and IL transitions in the ultraviolet region, appear. The spectra of [Ru(NH3)5(t-bpe)](PF6)3, trans-[Ru(SO4)(NH3)4(t-bpe)]Cl•nH2O, trans-[Ru(SO4)(4-acpy)(NH3)4]Cl•nH2O, trans-[Ru(NH3)4(H2O)(t-bpe)](PF6)3 and [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(SO4)(NH3)4](PF6)5•nH2O displayed a ligand-metal charge transfer (LMCT) transition in the region from 300 to 400 nm and, IL transitions below 300 nm. The spectra of the compounds trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O and [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O showed absorption bands in the 320 nm region with molar absorptivity around 2.8,10-4 L mol-1 cm-1, assigned to several transitions such as ligand field (LF), ligand-ligand charge transfer (LLCT), IL and metal-ligand charge transfer. The pKa values for the desprotonation of t-bpeH+ in [RuII(NH3)5(t-bpeH)]3+ (pKa 5,1), [RuIII(NH3)5(t-bpeH)]4+ (pKa 3,6), trans-[RuII(NH3)5(H2O)(t-bpeH)]3+ (pKa 4,5), trans-[RuIII(NH3)4(H2O)(t-bpeH)]4+ (pKa 2,8) and trans-[Ru(NO)(NH3)4(t-bpeH)]4+ (pKa 2,3) were determined. For the ruthenium(III) complexes, [RuIII(NH3)5(t-bpeH)]4+ and trans-[RuIII(NH3)5(H2O)(t-bpeH)]4+, the pKa values were smaller than in the ruthenium(II) complexes, [RuII(NH3)5(t-bpeH)]3+ and trans-[RuII(NH3)5(H2O)(t-bpeH)]3+. The pKa for trans-[Ru(NO)(NH3)4(t-bpeH)]4+ was the smallest one indicating a Ru(III) character for ruthenium. The 1H NMR spectrum of [Ru(NH3)5(t-bpe)](PF6)2 showed 3 signals from 8,6 to 7,6 ppm, with 4:4:2 integration, assigned to aromatic and ethylenic protons of the t-bpe ligand. For trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O there are 5 signals with chemical shifts from 8,7 to 7,6 ppm due to the NO influence. One of them is a doubled doublet assigned to ethylenic protons. The spectrum of [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O, has 6 signal located from 8,8 to 7,2 ppm, with 2:2:4:2:2:2 integration. These are assigned to aromatic and ethylenic protons of the t-bpe and aromatic of the 4-acpy. Only Ru2+/3+ processes were observed in the cyclic voltammograms of [Ru(NH3)5(t-bpe)](PF6)2 (E1/2’ = +116 mV vs Ag/AgCl), trans-[Ru(NH3)4(H2O)(t-bpeH)](PF6)3 (E1/2’ = +165 mV vs Ag/AgCl), trans-[Ru(4-acpy)(NH3)4(H2O)](PF6)2 (E1/2’ = +247 mV vs Ag/AgCl) and trans-[Ru(4-acpy)(NH3)4(t-bpe)](PF6)2 (E1/2’ = +405 mV vs Ag/AgCl). The cyclic voltammograms trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O and [trans-Ru(4-acpy)(NH3)4(-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O displayed {RuNO}3+/{RuNO}2+ processes (Ec = -170 mV vs Ag/AgCl and Ec = -188 mV vs Ag/AgCl, respectively) and cathodic peaks indicating {RuNO}2+/{RuNO}+ processes (Ec = -640 mV vs Ag/AgCl and Ec = -650 mV vs Ag/AgCl, respectively). The compound trans-[Ru(NO)(NH3)4(t-bpe)](PF6)3•H2O was irradiated at 313 and 366 nm, at pHs 1,2 and 7,0. Uv-vis and infrared spectrophotometries were used to analyze the product of the photochemical reaction. The decrease of the absorption band, NO, indicated the NO released. The quantum yields were determined for irradiations in 313 nm at pH 1,2 and 7,0 (0,10 and 0,12, respectively) and irradiations in 366nm at pH 1,2 and 7,0 (0,04 and 0,04, respectively) and are in agreement with those of other trans-[Ru(NO)(NH3)4(L)]3+ (L = py-X) complexes. Very promising preliminary photochemical results showed that irradiation of [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O with ultraviolet or visible light result in NO release. The data set showed a weak electronic communication between the extremities of t-bpe and that the NO release from [trans-Ru(4-acpy)(NH3)4(mu-t-bpe)trans-Ru(NO)(NH3)4]Cl5•2H2O with visible light is a result of that weak communication which causes visible light absorption by the binuclear complex. Thus, this class of complexes is very promising for the development of NO donors directed for biological applications, such as photochemical therapy.

La tularémie est une zoonose liée à la bactérie Francisella tularensis, hautement pathogène pour l’homme. La sous espèce la plus virulente, F. tularensis subsp. tularensis, est retrouvée uniquement en Amérique du Nord, alors que la sous-espèce F. tularensis subsp. holarctica est présente dans tout l’hémisphère Nord. En France toutes les souches appartiennent au biovar I de la sous-espèce holarctica et plus précisément au groupe phylogénétique B.FTNF002-00. Bien que rarement grave en France, la tularémie pose le problème de taux d’échecs thérapeutiques élevés, jusqu’à 25% en cas de traitement par ciprofloxacine ou gentamicine, et 35% pour la doxycycline. Les causes de ces échecs ne sont pas bien élucidées à l’heure actuelle. L’analyse de la littérature ainsi que la détermination de la sensibilité de 59 souches françaises de F. tularensis subsp. holarctica à 18 antibiotiques, confirment qu’aucune souche isolée à ce jour ne présente de résistance acquise à ces trois familles d’antibiotiques, qui représentent le traitement de première ligne de la tularémie. Les fluoroquinolones (en particulier la ciprofloxacine et la lévofloxacine) présentent concentrations minimales inhibitrices les plus basses, devant la gentamicine et la doxycycline. Les données disponibles in vitro et en modèle animal étant corrélées aux données humaines en termes d’efficacité et de taux d’échecs thérapeutiques, il semble néanmoins préférable de positionner la ciprofloxacine en première ligne pour le traitement des formes modérées de tularémie et de limiter l’utilisation de la doxycycline aux cas de contre-indication aux fluoroquinolones. L’azithromycine et la télithromycine ont été identifiées comme des alternatives thérapeutiques envisageables en cas d’infection par une souche de biovar I de F. tularensis subsp. holarctica lorsqu’existe une contre-indication aux traitements de première ligne. Des études en modèles animaux restent néanmoins nécessaires pour conforter ces dernières observations. La sélection in vitro de souches résistantes aux fluoroquinolones est possible, ce qui suggère la possibilité d’émergence de mutants résistants in vivo pour expliquer les taux d’échec thérapeutiques. Les principales mutations de résistance aux fluoroquinolones chez F. tularensis sont observées au niveau des gènes gyrA et gyrB codant pour les topoisomérases de type II. L’impact fonctionnel de mutations de résistances aux fluoroquinolones a été caractérisé in vitro chez F. novicida, pris comme modèle de bactérie avirulente proche de F. tularensis. L’activité de superenroulement et de clivage de l’ADN en présence de fluoroquinolones a été déterminée suite à la reconstruction in vitro de complexes GyrA/GyrB fonctionnels. La résistance aux fluoroquinolones était la plus forte en cas de mutation D87G/D87Y pour la sous-unité GyrA ou +P466 pour la sous-unité GyrB. La mutation P43H située en dehors du QRDR de GyrA est à l’origine d’un plus faible niveau de résistance. La mutation D487R-∆K488 en dehors du QRDR de GyrB ne confère pas de résistance intrinsèque mais potentialise l’effet d’une mutation D87G concomitante. En revanche, l’identification de mutations de résistance in vivo au sein des QRDR des gènes gyrA et gyrB chez des patients en situation d’échec thérapeutique traités par une fluoroquinolone est demeurée négative. Enfin, notre recherche a permis d’identifier de nouveaux composés de synthèse de structure bis-indolique possédant des activités antibactériennes. Ces composés sont bactériostatiques vis-à-vis de F. tularensis mais bactéricides vis-à-vis des staphylocoques y compris vis-à-vis de souches multi-résistantes de Staphylococcus aureus avec des CMI90 évaluées à 2mg/L chez F. tularensis et S. aureus pour le composé le plus actif. La faible solubilité de ces composés en milieu aqueux, leur forte liaison aux protéines plasmatiques ainsi que la recherche de leur mécanisme d’action original appellent néanmoins de nombreux développements futurs. / Tularemia is a zoonosis caused by the highly pathogenic bacterium Francisella tularensis. The most virulent subspecies, F. tularensis subsp. tularensis, is found only in North America while the subspecies F. tularensis subsp. holarctica is present in the whole Northern hemisphere. In France, all strains belong to the biovar I of the subspecies holarctica and more specifically to the phylogenetic subclade B.FTNF002-00. Although tularemia is usually not a severe disease in France, many patients suffer from therapeutic failures despite receiving an appropriate treatment. These treatments failures are observed in up to 25% of patients treated with ciprofloxacin or gentamicin, and up to 35% if patients treated with doxycycline. The causes of those therapeutic failures remain poorly elucidated. Analysis of the literature and determination of the susceptibility of 59 French F. tularensis subsp. holarctica strains to 18 antibiotics confirmed that to date, no strain with acquired resistance to any of the first-line antibiotics used for treatment of tularemia have been isolated. The fluoroquinolones (in particular ciprofloxacin and levofloxacin) exhibit the lowest minimal inhibitory concentrations, compared to gentamicin and doxycycline. Data obtained in vitro and in animal models are concordant with human data concerning the efficacy of antibiotics and therapeutic failure rates. Thus, we advocate the use of ciprofloxacin as first-line treatment for mild form of tularemia, and the use of doxycyclin only as a second-line treatment in patients with contraindications to fluoroquinolones. Azithromycin and telithromycin may also be considered as potential therapeutic alternatives for tularemia cases caused by biovar I strains of the susbspecies holarctica, but only for patients with contraindications to first-line antibiotics. Further data in animal models are however required to consolidate our in vitro data. The in vitro selection of fluoroquinolone-resistant strains of F. tularensis has been reported. This suggests that the in vivo selection of such resistant mutants may occur. In vitro, the main fluoroquinolone resistance mutations occur in the gyrA and gyrB genes that encode type II topoisomerases of F. tularensis. We have characterized the functional impact of such mutations in avirulent F. novicida strains, taken as a surrogate of F. tularensis. Supercoiling and DNA cleavage activity of GyrA/GyrB complexes reconstituted in vitro have been determined in the presence of fluoroquinolones. Fluoroquinolone resistance level was the highest in strains with a D87G/D87Y mutation in the GyrA subunit or +P466 mutation in the GyrB subunit. The mutation P43H located outside the GyrA Quinolone-Resistance-Determining-Region (QRDR) confered significant but lower fluoroquinolone resistance. The mutation D487R-∆K488 also outside GyrB QRDR did not cause fluoroquinolone resistance by itself, but increased the resistance level in case of concomitant D87G mutation. No mutation could be identified in vivo in the QRDR of gyrA and gyrB genes amplified from clinical samples collected in patients treated with a fluoroquinolone, although some of them experienced therapeutic failure. Finally, while searching for new antibiotic compounds, we identified new synthetic bis-indolic derivatives with antibacterial activity. Lead compounds were only bacteriostatic against F. tularensis but bactericidal against staphylococci including against multi-drug-resistant Staphylococcus aureus. MIC90 were measured at 2mg/L for F. tularensis and S. aureus strains for the most active compound. However, many developments are still required to improve their solubility in water, decrease their plasma proteins binding and elucidate their original mechanism of action.

O objetivo deste trabalho é explorar a síntese e funcionalização de 1,2,3- triazóis empregando o uso de reações do tipo \"Click-chemistry\", que é uma abordagem para a síntese de diversos compostos com base em reações de formação de ligação carbono-heteroátomo, onde a reação é estereoespecífica, altamente eficiente e geralmente com elevados rendimentos e em alguns casos ausência de subprodutos. O composto 1,2,3-triazol, sendo o material de partida para a continuidade do projeto foi preparado a partir do álcool propargílico (4) em presença de uma azida orgânica (1) e utilizando cobre(I) como agente promotor. Após a obtenção de uma série de compostos 1,2,3-triazólicos (2), procedeu-se a etapa de tosilação da hidroxila e posterior cicloadição multicomponente de um novo 1,2,3-triazol formando compostos bis-triazólicos. Os bis-triazóis (5) obtidos foram testados frente a cepas fúngicas, responsáveis por dermatites, com resultados satisfatórios. Ainda essas estruturas poderão ser empregados como blocos construtores para a síntese de estruturas mais complexas. / The aim of this work has been exploring the synthesis and functionalization of 1,2,3-triazoles employing the use of \"click-chemistry\" concept, which is defined as an approach for synthesis of various compounds based on reactions of carbon-heteroatom bond formation, which the reaction is stereospecific, high-efficiently, commonly gives high yields and in some cases no by-products are formed. The compound 1,2,3-triazole, which is the main starting material for the next steps was prepared from propargyl alcohol (4) in the presence of an organic azide (1) and copper(I) as a reaction promoter. Subsequently with a series of 1,2,3-triazole (2n) prepared we proceeded to the next step which is the substitution of hydroxyl for a tosyl group and after that a multicomponent cycloaddition of a new 1,2,3-triazole compound forming bis-triazoles. Bis-triazoles (5) were tested against fungal strains, responsible for dermatitis, with delighted results, furhtermore this class of strutures can be used as building blocks to improve efficiency in some other more complex structure.

La réaction de cyclisation de type Wacker, de composés polyols et aminopolyols insaturés constitue un outil puissant et efficace pour la synthèse d’hétérocycles oxygénés ou azotés.Dans ce travail de thèse, nous proposons l’étude d’une réaction catalysée par un complexe de palladium(II) de type domino-cyclisation, mettant en jeu une réaction de couplage. Cette séquence catalytique revient à une fonctionnalisation d’un hétérocycle par une chaîne latérale, tout en créant deux centres stéréogènes en une seule étape. L’influence de la nature des réactifs mis en jeu, ainsi que des conditions expérimentales sur l’activité et la diastéréosélectivité de la réaction sont discutées. Les applications vers la synthèse de produits naturels (anisomycine) ou d’analogues (varitriol) sont présentées.La réaction d’oxycarbonylation catalysée par un complexes de palladium(II) est une transformation intéressante de polyols insaturés en lactones bicycliques, présentant un motif de type tétrahydrofurane avec une excellente stéréosélectivité-cis. Le premier exemple de réaction d’oxycarbonylation catalysée par des complexes de palladium chiraux dans les liquides ioniques est décrit. Une étude approfondie de la nature des ligands démontre que les bis(oxazolines) chirales constituent les meilleurs ligands du palladium pour la cyclisation du pent-4-ène-1,3-diol racémique 69a. Le dédoublement cinétique du composé 69a sous atmosphère de monoxyde de carbone, en présence d’un complexe chiral de palladium(II) et de p-benzoquinone employant l’acide acétique ou le liquide ionique [bmim]NTf2 comme solvant, a permis d’isoler le 2,6-dioxabicyclo-[3.3.0]octane-3-ones avec jusqu’à 57% d’excès énantiomérique pour l’énantiomèrede configuration (R,R)-70a, et jusqu’à 80% d’excès énantiomérique pour l’énantiomèrede configuration (S,S)-70a. / Intramolecular Wacker-type cyclization of unsaturated polyols and aminopolyols represents a powerful method in the synthesis of oxygen- or nitrogen-containing heterocycles. The thesis offers an insight into the systematic study of domino intramolecular palladium(II)-catalyzed cyclization and coupling reaction allowing the implementation of side chains into heterocyclic skeletons along with the formation of two stereocenters in a single step. Different types of coupling partners and reaction conditions were examined, the influence of substrate substituents on diastereoselectivity is discussed. The applications in the synthesis of naturally occuring compounds or their analogs are outlined (anisomycin, varitriol). Palladium(II)-catalyzed oxycarbonylation represents an interesting transformation of unsaturated polyols into bicyclic lactones with tetrahydrofuran structural motif with excellent cis-stereoselectivity. The first example of the use of ionic liquids as reaction media in the asymmetric Pd(II)-catalyzed oxycarbonylation is described. Based on a ligand screening, the chiral bis(oxazoline)-type ligands were successfully used in the Pd(II)-promoted bicyclisationof racemic pent-4-ene-1,3-diol (±)-69a. The kinetic resolution of (±)-69a in the presenceof chiral catalyst and p-benzoquinone under carbon monoxide atmosphere using acetic acid and/or ionic liquid as solvent afforded enantioenriched 2,6-dioxabicyclo[3.3.0]octane-3-ones(R,R)-70a (57% ee) and (S,S)-70a (80% ee), respectively.

Submitted by Maria Aparecida (cidazen@gmail.com) on 2017-11-16T13:16:54Z No. of bitstreams: 1 JOSÉ RIBAMAR NASCIMENTO DOS SANTOS.pdf: 1283725 bytes, checksum: 4c5d6eba4cec82d8cb883aa89b0a81f6 (MD5) / Made available in DSpace on 2017-11-16T13:16:54Z (GMT). No. of bitstreams: 1 JOSÉ RIBAMAR NASCIMENTO DOS SANTOS.pdf: 1283725 bytes, checksum: 4c5d6eba4cec82d8cb883aa89b0a81f6 (MD5) Previous issue date: 2017-09-19 / CAPES / The electro-oxidation of ethanol was evaluated on a pyrolytic graphite electrode (PGE) chemically modified with the nickel(II)-bis(1,10-phenanthroline) complex (Ni(II)(Phen)2) supported on reduced graphene oxide (RGO) (rGO/Ni(II)(Phen)2/PGE). The Ni(II)(Phen)2 complex, reduced graphene oxide (rGO) and the rGO/Ni(II)(Phen)2 composite were prepared and characterized by the techniques of Spectroscopy in the UV-Vis, Fourier Transform Infrared Spectroscopy and Diffraction of X-rays. The electrocatalytic activity of the material was evaluated by cyclic voltammetry and chronoamperometry. In alkaline solution, the voltamograms obtained for rGO/Ni(II)(Phen)2/PGE showed the formation of well defined redox peaks associated with the Ni(II)/Ni(III) redox couple. The results showed that the RGO/Ni(II)(Phen)2 composite significantly increases the electrocatalytic activity for ethanol oxidation compared to the electrode modified only with the Ni(II)(Phen)2 complex. Using the Laviron theory, the charge transfer rate constant (ks) and the electron transfer coefficient (α) of the electrode reaction were calculated to be 0.56 s-1 and 0.61, respectively. A investigation of the electro-oxidation of ethanol was performed by evaluating the effect of different parameters such as potential scan rate, OH- concentration and alcohol concentration. The chronoamperometric experiments were used to determine the diffusion coefficient of ethanol (D = 4.7 Χ 10-6 cm2 s-1) and the catalytic rate constant (kcat = 1.26 Χ 107 cm3 mol-1 s-1). The results obtained in this study clearly indicate the viability of rGO/Ni(II)(Phen)2/PGE as an electrocatalyst for ethanol oxidation. / A eletro-oxidação do etanol foi avaliada em um eletrodo de grafite pirolítico (PGE) quimicamente modificado com o complexo de níquel(II)-bis(1,10-fenantrolina) (Ni(II)(Phen)2) suportado em óxido de grafeno reduzido (rGO) (rGO/Ni(II)(Phen)2/PGE). O complexo Ni(II)(Phen)2, o óxido de grafeno reduzido (rGO), e o compósito rGO/Ni(II)(Phen)2 foram preparados e caracterizados pelas técnicas de Espectroscopia na região do UV-Vis, Espectroscopia de Infravermelho com Transformada de Fourier e Difração de Raios X. A atividade eletrocatalítica do material foi avaliada por voltametria cíclica e cronoamperometria. Em solução alcalina, os voltamogramas obtidos para rGO/Ni(II)(Phen)2/PGE mostraram processos redox bem definidos associados ao par redox Ni(II)/Ni(III). Os resultados mostraram que o compósito rGO/Ni(II)(Phen)2 aumenta significativamente a atividade eletrocatalítica para a oxidação do etanol em comparação com o eletrodo modificado apenas com o complexo Ni(II)(Phen)2 adsorvido na superfície do eletrodo. Usando a teoria de Laviron, a constante de velocidade de transferência de carga (ks) e o coeficiente de transferência de elétrons (α) da reação do eletrodo foram calculados sendo 0,56 s-1 e 0,61, respectivamente. Uma investigação da eletro-oxidação do etanol foi realizada avaliando o efeito de diferentes parâmetros, como a velocidade de varredura do potencial, a concentração de OH- e a concentração de álcool. Os experimentos cronoamperométricos foram utilizados para determinar o coeficiente de difusão do etanol (D = 4,7 Χ 10-6 cm2 s-1) e a constante de velocidade catalítica (kcat = 1,26 Χ 107 cm3 mol-1 s-1). Os resultados obtidos neste estudo indicam, claramente, a viabilidade do rGO/Ni(II)(Phen)2/PGE como eletrocatalisador da oxidação de etanol.

Ce travail démontre l'utilité des propriétés photothermiques dans le proche Infrarouge (NIR) des complexes de nickel-bis(dithiolène) neutres pour des applications en science des matériaux et biotechnologies. Des complexes Ni-bis(dithiolène) neutres hydrophiles et hydrophobes ont été élaborés et leur effet photothermique, sous irradiation laser NIR, a été quantifié pour la première fois. Grâce à cette propriété remarquable et à leur grande stabilité sous irradiation, il a été mis en évidence, que ces complexes pouvaient trouver des applications pour la thérapie photothermique, la libération contrôlée de médicament mais également pour le développement de nanomatériaux photosensibles à un stimulus externe. En effet, cet effet photothermique, sous irradiation laser NIR, permet de détruire des cellules cancéreuses, d'augmenter la perméabilité de nanoparticules polymériques ou de liposomes contenant des principes actifs et de désagréger des métallogels à base de complexes Ni-bis(dithiolène). Enfin, nous avons montré que les complexes [Ni(R2-timdt)2]0 ayant une haute efficacité photothermique sont de nouveaux candidats très prometteurs pour ce type d'applications. / The photothermal properties in the near Infrared (NIR) of neutral nickel-bis(dithiolene) complexes were used in materials science and for the first time in biotechnology. Hydrophilic and hydrophobic neutral Ni-bis(dithiolene) complexes were developped and for the first time, their photothermal effect under NIR laser irradiation was quantified. Thanks to this remarkable property and their high stability under irradiaton, it has been demonstrated that these complexes could find applications to photothermal therapy, controlled drug delivery but also in the developpement of stimuli responsive nanomaterials. Indeed, this photothermal effect, under NIR laser irradiation, allow to destroy malignant cells, increase the permeability of polymeric nanoparticles or liposomes containing active ingredients and disintegrate métallogels based on Ni-bis(dithiolene) cores. Finally, we showed that the [Ni(R2-timdt)2]0 complexes having higher phothothermal activity are very promising new candidates for these applications.

Nous avons etudié la réduction des fonctions carbonyles de dicétals dilactames qui sont engendrées à partir d'hydroxyamidoacétals. Ces derniers sont obtenus à partir de béta-aminoalcools. Cette réduction nous a permis d'isoler 6 dicétals amino-lactames (composés monoréduits) et 6 dicétals diamines (composés diréduits), homologues dioxygénés des cyclames. Nous avons montré que la facilité de la réduction dépend de la nature des substituant et de la stéréochimie cis ou trans des groupements OMe: les dérivés cis étant plus faciles à réduire que les dérivés trans. Les dicetals amino-lactames sont obtenus à des concentrations faibles( 3 à 14x10-3M) et les dicétals diamines à des concentrations plus élevées (15 à 30 x 10-3M). L'étude des propriétés complexantes des différentes molécules synthétisées vis-à-vis du radioélément technetium-99m (99mTc) montre que seuls les dicétals diamines se prêtent à une complexation avec des pourcentages maximum de 18%. Les études d'accès aux composés dimères ont permis d'isoler 5 bis-dicétals amino-lactames et 2 bis-dicétals diamines , homologues des bicyclames à activité anti-virale.

Die vorliegende Arbeit befasst sich mit der Darstellung mono-, bi- und trimetallischer bis(oxamato) und bis(oxamidato) Übergangsmetallkomplexe, ihrer - insbesondere - magnetischen Charakterisierung, der Überführung trimetallischer Komplexe in dünne Filme im nm-Bereich mittels Rotationsbeschichtung auf Si/SiO2-Substraten, der Charakterisierung der Filme und magneto-optischen Untersuchungen der dünnen Filme. Durch gezielte Variation funktioneller Gruppen insbesondere der trimetallischen bis(oxamato)-Übergangsmetallkomplexe, wie der Verwendung variierter zentraler N,N’-Brücken, terminaler Liganden bzw. inkorporierter Übergangsmetallionen sollten nicht nur die physikalischen Eigenschaften modifiziert werden, sondern auch das Abscheideverhalten dieser Komplexe beim Überführen in dünne Filme.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal