Submitted by Sandro Camargo (sandro.camargo@unipampa.edu.br) on 2015-05-08T03:06:29Z No. of bitstreams: 1 127110046.pdf: 2895137 bytes, checksum: edf417bbba917e277ef644cfa24efbf9 (MD5) / Made available in DSpace on 2015-05-08T03:06:29Z (GMT). No. of bitstreams: 1 127110046.pdf: 2895137 bytes, checksum: edf417bbba917e277ef644cfa24efbf9 (MD5) Previous issue date: 2014-07-21 / As chalconas são compostos de origem vegetal e apresentam estrutura química simples que é amplamente utilizada como molécula protótipo para a obtenção de novos compostos bioativos através de modificações estruturais nos seus anéis aromáticos. Este fato é importante uma vez que a Sociedade Americana de Doenças Infecciosas lançou a iniciativa “10 x 20”, ou seja, o rápido desenvolvimento de 10 novos antibióticos até o ano de 2020. O objetivo deste estudo é a obtenção e determinação das propriedades físico-químicas e biológicas de chalconas com atividade antibacteriana potencial. As moléculas foram planejadas utilizando-se a metodologia de bioisosterismo clássico de valência, propondo a alteração da hidroxila presente na posição 4 do anel A da Licochalcona pelo grupo amino; no anel B houve a introdução de grupos nas posições para e meta, com graus variáveis de efeito eletrônico, de acordo com o emprego do Diagrama de Craig. As aminochalconas substituídas foram sintetizadas pela reação de Claissen-Schimdt, com quantidades equimolares de 4- aminoacetofenona e benzaldeídos variados e purificadas via cromatografia em coluna ou recristalização para posterior caracterização por espectroscopia de infravermelho e ressonância magnética nuclear. A avaliação da atividade antibacteriana e sinérgica foi realizada através do método de microdiluição em caldo descrito pelo Clinical and Laboratory Standards Institute e Teste de checkerboard frente a cepas referências de bactérias gram- positivas e gram-negativas (Staphylococcus aureus ATCC 29213 e Escherichia coli ATCC 25922), além de uma cepa S. aureus resistente à meticilina (N315). Foi utilizado o programa computacional Spartan ́08 for Windows para determinação da estrutura química em 3D e cálculo dos valores das energias de HOMO e LUMO. O estudo teórico das propriedades físico-químicas foi realizado pelos programas Chem3D Ultra, Molinspiration e MarvinSketch 6.2. Para o estudo teórico da toxicidade e dos perfis de druglikeness e drugscore empregou-se o programa Osiris Property Explorer. Os compostos 1, 3 e 7 apresentaram os menores valores de CIM quando ensaiados frente a ambas cepas de S. aureus, o que sugere que o mecanismo de resistência bacteriana não afeta a atividade desempenhada pelas 4-aminochalconas. Os compostos 5 e 8 foram os mais ativos frente a cepas E. coli. Não houve interação significativa entre as 4-aminochalconas e os antibióticos testados (oxacilina e cloranfenicol). Através da avaliação das relações estrutura-atividade, verificou-se que o composto 8 apresentou vários parâmetros que podem justificar sua ação frente a bactérias gram-negativas, como peso molecular elevado e menores valores de cLogP e LogD 7.4 . Resultados superiores à levofloxacina foram também evidenciados quando calculado seu potencial de druglikeness e de drugscore. Todos os compostos apresentaram alto risco teórico para o efeito mutagênico e baixo perfil toxicológico para o efeito irritante. Em relação aos efeitos no sistema reprodutor, apenas o composto 1 apresentou um risco médio, e para os compostos 2 e 3 foi descrito alto risco para o efeito tumorogênico. Mesmo apresentando uma atividade antibacteriana baixa, estas moléculas podem vir a delinear modificações estruturais com o intuito de aumento da ação biológica, visto que todas enquadram-se dentro dos parâmetros delineados na Regra dos Cinco e, devido a isso, são promissoras a apresentar uma boa biodisponibilidade oral. / Chalcones are vegetal origin compounds and they present a simple chemical structure which is widely used as a molecule prototype in order to obtain new bioactive compounds by structural changes in their aromatic rings. Such fact is important as the American Society of Infectious Diseases has released the “10 x 20” initiative, meaning the fast development of 10 new antibiotics up to 2020. This study aims to obtain and establish chalcone’s physical- chemical and biological properties with potential antibacterial activity. The molecules were designed by the classic bioisosterismo classic methodology, proposing the modification of the hydroxyl existent in licochalcone’s position 4 of ring A in the amino group, in ring B groups were introduced in para and meta positions, with variable degrees of electronical effects, according to the usage of Craig ́s Diagram. The replaced aminochalcones were synthesized by the Claissen-Schimdt reaction with equimolar quantities of 4-aminoacetophenone and varied benzaldehydes and purified by column chromatography or recrystallization for further characterization by infrared spectroscopy and nuclear magnetic resonance. The evaluation of the antibacterial and synergic activity was made through Microdilution Methods described by the Clinical and Laboratory Standards Institute and checkerboard test against reference strains of gram-positive and gram-negative (Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922), plus S. aureus meticillin resistant (N315). Spartan’08 for Windows was the computational program used to establish the 3D chemical structure and the HOMO’s and LUMO’s energy amount figures. The theoretical study of Physical-chemical properties was accomplished by Chem3D Ultra, Molinspiration and MarvinSketch 6.2 programs. In order to theoretically study both toxicity and profile of druglikeness and drugscore, Osiris Property Explorer program was used. The compounds 1, 3 and 7 showed the smallest CIM values when against both S. aureus strains, which suggests that the bacterial resistance mechanism doesn’t affect the 4-aminochalcones activity. Compounds 5 and 8 were more actives against strains E. coli. There was no significant interaction among the 4- aminochalconas and the antibiotics tested (oxacilin and chloramphenicol). Throughout the structural-activity relation evaluation, it was verified that compound 8 presented several parameters that may justify its action facing Gram-negative bacteria, such as the growth of its molecular weight and decreased values of cLogP and LogD7,4 . Levofloxacin superior results were also certified when its potential of druglikeness and drugscore were figured. All the compounds have presented a high theoretical risk to the mutagenic effect and low toxicological profile to the irritant effect. Relating to the effects in the reproductive system, only compound 1 has presented a mid-risk and compound 2 and 3 high risk to tumorigenic effect. Even though these molecules have showed low antibacterial activity, they might outline changes in their structure aiming the biological action growth as they all fit the Rule of Five parameters and as a result, they tend toward a good oral bioavailability.

El objetivo principal de esta tesis es la síntesis de polímeros empleando aceites vegetales como reactivos de partida. En la primera parte, se prepararon diferentes polímeros termoestables por modificación química de aceite de girasol alto oleico y posterior polimerización via aza-Michael y radicalaria. Se ha realizado un estudio exhaustivo del mecanismo de entrecruzamiento por reacción aza-Michael pudiéndose comprobar que variando la temperatura de entrecruzamiento y añadiendo un ácido de Lewis como catalizador se produce la formación de anillos de tipo quinolina como puntos de entrecruzamiento. En la segunda parte, se empleó aceite de girasol alto oleico para sintetizar polímeros entrecruzados con grupos funcionales fosforados que mostraron propiedades de retardancia a la llama. Se empleó la polimerización por metátesis acíclica de dienos (ADMET) para la síntesis de polímeros lineales y entrecruzados con grupos funcionales fosforados empleando ácido 10-undecenoico (derivado del aceite de ricino). Estos polímeros presentaron propiedades de retardancia a la llama. Como conclusión general, se puede afirmar que se emplearon aceites vegetales y sus derivados como reactivos para la síntesis de materiales poliméricos de manera satisfactoria. / The main objective of this thesis is the synthesis of polymers using as starting reagents plant oil based chemicals. In the first part, different thermosetting polymers were synthesized through chemical modifications of commercial high oleic sunflower oil followed by cross-link via aza-Michael addition and radical polymerization. A thorough study of the aza-Michael cross-link reaction with model compounds showed that depending on the temperature and the presence of a Lewis acid catalyst quinoline rings can be formed as cross-link points. In the second part, high oleic sunflower oil was used for the synthesis of cross-linked polymers containing phosphorus functional groups via radical polymerization that showed improved flame retardancy. Acyclic diene metathesis (ADMET) polymerization was used for the synthesis of linear and cross-linked polymers with phosphorus containing functional groups using 10-undecenoic acid (castor oil derived). These polymers showed and improved flame retardancy. As a general conclusion, plant oils could be used as renewable reagents for the synthesis of linear and cross-linked polymers.

Dans le contexte du développement des bio-raffineries, le glycérol et ses dérivéssont des co-produits de l’oléochimie pour lesquels de nouvelles voies de valorisation doiventêtre trouvées. Cette thèse porte sur l’étude de la polymérisabilité d’un dérivé du glycérol, ledivinylglycol (DVG), monomère symétrique à 6 carbones qui possède un diol vicinal et deuxfonctions vinyliques. Dans ces travaux, la réactivité des fonctions hydroxyle et vinyliques duDVG dans des réactions de polycondensation et polyaddition a été investiguée. Dans unpremier temps, la synthèse de polyesters et de polyuréthanes a été réalisée par réaction duDVG avec des diesters biosourcés et des diisocyanates, respectivement. Les fonctionsvinyliques du DVG ont ensuite été mises à profit pour synthétiser des polymères originaux parpolymérisation par ADMET et addition thiol-ène. Enfin, des réseaux tridimensionnels époxyamineont été préparés par polymérisation entre une série de diamines et le DVG bis-époxydé,préalablement obtenu par oxydation des doubles liaisons. Ces différentes méthodes depolymérisation ont montré que les doubles liaisons du DVG étaient plus réactives que lesfonctions alcool et qu’un panel de polymères originaux pouvait être obtenu à partir de cesynthon bio-sourcé. / In the context of the development of bio-refineries, glycerol and its derivatives areco-products of oleochemistry for which new valorization routes must be found. This thesisdeals with the polymerizability study of a glycerol derivative, divinylglycol (DVG), asymmetrical C-6 monomer which bears a vicinal diol and two vinyl functions. In this work, thereactivity of the hydroxyl and vinyl functions of DVG in polycondensation and polyadditionreactions was studied. In a first step, the synthesis of polyesters and polyurethanes wascarried out by reaction of DVG with biosourced diesters and diisocyanates, respectively. Thevinyl functions of DVG were then used to synthesize original polymers by ADMETpolymerization and thiol-ene addition. Finally, three-dimensional epoxy-amine networkswere prepared by polymerization between a series of diamines and the bis-epoxidized DVG,previously obtained by oxidation of the double bonds. These different methods ofpolymerization showed that DVG double bonds were more reactive than the alcohol functionsand that a panel of original polymers could be obtained from this bio-sourced synthon.

Ces travaux de thèse traitent de l’utilisation d’une molécule polycyclique, l’acide abiétique, issu de la colophane, et de dérivés phénoliques potentiellement dérivés de la lignine, pour la synthèse de polymères rigides bio-sourcés. Dans les deux cas, des monomères symétriques et difonctionnels sont élaborés par réaction de dimérisation des précurseurs bio-sourcés puis testés en polymérisation. D’une part, les dimères de l’acide abiétique obtenus par un mécanisme cationique possèdent des structures mal définies qui compliquent leur polymérisation. Ces dimères ont alors été estérifiés avec de l’undécénol afin d’obtenir un composé bis-insaturé qui est ensuite polymérisé par ADMET. D’autre part, un procédé de dimérisation de molécules phénoliques, potentiellement issues de la lignine, a été développé par voie enzymatique utilisant une laccase. L’avantage majeur de ce procédé ‘vert’ réside dans la séparation très simple entre le monomère, soluble, et son dimère, insoluble. Ces dimères ont ensuite été modifiés chimiquement afin de constituer une bio-plateforme de composés biphényles fonctionnels. Ces composés ont été utilisés pour la synthèse de polyesters, polyamides et résines époxy qui présentent des propriétés thermiques et thermomécaniques remarquables. / The aim of this thesis is to investigate new biobased rigid synthons for the synthesis of polymers with high thermomechanical properties. A polycyclic biobased molecule, i.e resinic acids, and phenolic compounds potentially derived from lignin, such as vanillin were selected. Both classes of substrates were dimerized in order to get difunctional symmetric synthons. On the one hand, abietic acid dimers synthesized via a cationic mechanism presented an ill-defined structure. To avoid reactivity issues, dimers with reactive terminal double bonds were successfully synthesized by esterification of abietic acid dimers with undecenol and polymerized by ADMET methodology. On the other hand, we developed a “green” process to dimerize phenolic compounds derived from lignin in large quantity and high yield via enzymatic catalysis using a laccase. The main advantage of this method is that the phenolic monomer is soluble in the reaction medium while the dimer precipitates. After chemical modifications of the dimers, we built a functional bio-platform of biphenyl derivatives. The latter were then used for the synthesis of polyesters, polyamides and epoxy resins which exhibited remarkable thermal and thermomechanical properties.

L´objectif du travail présenté dans ce manuscrit consiste à conserver les bonnes propriétés mécaniques du poly(butadiène) dihydroxytéléchélique (PBHT) tout en améliorant sa stabilité. Un des principaux verrous techniques de cette approche réside dans le fait que les doubles liaisons responsables la flexibilité du matériau sont également la cause de son vieillissement par oxydation. Les solutions proposées reposent sur l´utilisation de la métathèse comme outils de synthèse de polymères insaturés. Deux grandes voix de synthèse ont été étudiées : la polymérisation par ouverture de cycle via métathèse (ROMP) ainsi que la dépolymerisation fonctionnalisante (ADMET). Ces deux approches bien que prometteuses n’ont pas permis de sortir de la relation ciseau existante entre flexibilité et stabilité. Finalement, une solution basée sur le mélange entre deux polymères dihydroxytéléchéliques de basse température de transition vitreuse – poly(butadiene) et poly(isobutylene) a permis de répondre dans une certaine mesure aux cahier des charges. En parallèle a ces parties synthèses, une étude physique des relations structure-propriétés visant à améliorer la stabilité des oligomères a été apporté par mesure rhéologique du temps critique de réticulation. / The work reported in the following document is aiming at maintaining the good mechanical properties of diHydroxyTelechelic PolyButadiene HTPB while improving its stability. The major challenge of this approach is that the unsaturations responsible for the outstanding flexibility of the material are also rather sensitive to oxidation. The solutions presented in this study are based on the use of metathesis reactions as a tool for the design of new difunctional unsaturated oligomers. Two functionalization techniques have been investigated, on the one hand, the Ring Opening Methathesis Polymerisation (ROMP) and, on the other hand, the depolymerisation via Acyclic Diene METathesis (ADMET). Although promising, the latters proved to fall into the vicious circle consisting in simultaneously increasing the stability while losing the flexibility. Finally, a blending concept based on the mixture of two dihydroxytelechelic polymers, namely, poly(isobutylene) and poly(butadiene), could enable us to achieve our initial goal. In addition to the chapters focusing on polymer chemistry and synthesis, a physical study of the parameters influencing the aging of unsaturated oligomers have been set-up and the properties relationship using measurements of the critical time.

In Book 1 of the Argonautica, Apollonios Rhodios counts out the names of 55 heroes who set off to win the Golden Fleece. All the heroes are given genealogical details that often contribute to their characterisation. Only Admetus’ γενεή is passed over in silence by the catalogue. This was noted already by H. Fränkel, who suspected a lacuna in the text. However, there is another solution to the problem. The distinctive relationship of Admetus to his parents is detailed nowhere more clearly and drastically than in Euripides’ Alcestis. In what is perhaps the most bitter agon in Greek tragedy, the father and son quarrel so severely that Admetus throws his parents out of the house and from then on wishes not to be regarded as their son. Apollonios assumes a knowledge of this famous quarrel among his readers or hearers, and he shows the sad consequences of this unreconciled generational conflict by breaking the convention of filiation and silently calling to mind the unresolved problems of the Alcestis.

The utilization of renewable sources as alternatives for petroleum and natural gas products has immense commercial, health and global warming significance. D-Isosorbide (2) is a bifunctional, polar, chiral and rigid molecule, which is produced from renewable sources. Synthesis of new polymers containing 2 is of interest for polymers and in drug delivery. The aim of the present work is to synthesize various polymers (homo- and copolymers) containing 2 via the olefin metathesis routes, ring-opening metathesis polymerization (ROMP) and acyclic-diene metathesis polymerization (ADMET). N-Phenyl-7-oxanorbornene-dicarboximide, and norbornene functionalized onto 2 were used as the monomers for ROMP. These monomers were polymerized using Grubbs’ catalysts to generate a series of homo-, co-, block and cross-linked-polymers. These polymers were characterized using GPC, NMR, and IR. In addition, ADMET polymerization of a terminal diolefinunctionalized D-isosorbide (2) was also conducted to produce ADMET polymers.

Ces travaux de thèse traitent de l’étude de glycolipides et plus précisément d’esters de trehalose pour la synthèse de nouveaux polymères bio-sourcés. Des monoesters et diesters de trehalose ont ainsi été synthétisés par estérification des alcools primaires du trehalose avec des acides gras selon deux voies de synthèse. La première utilisant un agent de couplage peptidique ne nécessite pas l’utilisation de groupement protecteur pour estérifier sélectivement les alcools primaires. La deuxième est une estérification sélective catalysée par une lipase. L’auto-assemblage des esters de tréhalose a ensuite été étudié. Les monoesters possèdent des propriétés tensio-actives dans l’eau et le trehalose monoeruçate a la capacité de gélifier l’eau. Les diesters, quant à eux sont de bons gélifiants pour les solvants organiques etles huiles végétales. Par conséquent, des gels ont été préparés dans trois huiles végétales, puis leur morphologie et leur propriété rhéologique ont été étudiées. Ensuite, les diesters ont été fonctionnalisé et polymérisés selon différentes stratégies. Ainsi, des polyuréthanes et des poly(hydroxyuréthane)s ont été synthétisés par polycondensation tandis que des glycopolyesters ont été obtenus par polymérisation par métathèse et addition thiol-ène. Finalement,les propriétés d’auto-assemblage de ces polymères ont été étudiées. Ces derniers peuvent former des nanoparticules par la méthode de déplacement de solvants. / The aim of this thesis was to study glycolipids and particularly trehalose esters for the synthesis of new bio-sourced polymers. Trehalose monoesters and diesters were synthesized by two esterification pathways of the primary alcohol of trehalose with different fatty acids. The first synthetic route is a protective group-free esterification using a peptide coupling agent and the second one is a lipase-catalyzed esterification. The self-assembly properties of the trehalose esters were investigated. Trehalose monoesters showed surfactant properties in water and trehalose monoerucate was even able to form gels in water. The trehalose diesters appeared to be good gelators for organic solvent and vegetable oil. Thus, gels in three vegetable oils were prepared and their morphology and rheological properties were studied. Afterwards, trehalose diesters were functionalized and polymerized with different strategies.Thus, polyurethanes and poly(hydroxyurethane)s were obtained by polycondensation where as glyco-polyesters were synthesized by acyclic diene metathesis (ADMET) and thiol-enepolymerization. Finally, the self-assembly properties of these polymers were investigated. The latter were able to form some nanoparticles by solvent displacement method.