La mise au point de réactions multicomposants métallo-catalysées permet de contribuer au développement d’une chimie plus verte. En effet, l’association des réactions multicomposants avec la catalyse, par la limitation du nombre d'étapes réactionnelles et de l'utilisation de réactifs toxiques, permet d’augmenter l’éco-compatibilité d’un procédé.L’application de ces principes a permis la synthèse cobalto-catalysée de dérivés β2,3-hydroxy- et β2,3-aminocarboxylés, composés d’intérêt croissant en chimie médicinale, à partir d'halogénures, d’accepteur de Michael et d’aldéhydes ou d’imines.Dans un premier temps, les conditions réactionnelles ont été optimisées puis l’étendue de la réaction a été étudiée afin de démontrer son caractère général. De plus, des études stéréochimiques et mécanistiques ont été réalisées par l’utilisation d’auxiliaires ou de catalyseurs chiraux de la réaction. La valorisation des composés synthétisés a également été entreprise par l'intermédiaire de réactions de post-condensation visant en particulier la synthèse d’hétérocycles. Enfin, la réaction multicomposants développée au cours de ce travail a contribué à l'établissement de nouvelles réactivités, permettant ainsi de développer l’utilisation du cobalt en synthèse organique / The elaboration of metallo-catalyzed multicomponent reactions contributes to the development of a greener chemistry. Indeed, the association of multicomponent reactions with catalysis, through the limitation of the number of reaction steps and the use of toxic reagents, allows to increase the eco-compatibility of a process.The application of these principles has enabled the cobalt-catalyzed synthesis of β2,3-hydroxy- et β2,3-aminocarboxylated derivatives, compounds of increasing interest in medicinal chemistry, starting from halogenated derivatives, Michael acceptors and aldehydes or imines.In a first part, the reaction conditions have been optimized and the scope of the reaction has then been studied to demonstrate its generality. Moreover, stereochemical and mechanistical studies have been realized by the use of chiral auxiliaries or catalysts in the reaction. The valorization of the prepared compounds has also been undertaken in post-condensation reactions in particular for the synthesis of heterocycles. The multicomponents reaction developed during this work has finally been extended to the elaboration of new reactivities, thus contributing to spread the use of cobalt in organic chemistry

Submitted by Lucas Michelão Martins (lmichelaomartins@yahoo.com) on 2018-04-18T20:57:09Z No. of bitstreams: 1 tese doutorado lucas m martins.pdf: 4956302 bytes, checksum: b3d6b99c6519511aa67ed77e0edb7e9d (MD5) / Rejected by Minervina Teixeira Lopes null (vina_lopes@bauru.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo; - inclusão do número de processo da FAPESP nos agradecimentos e campo de financiamento. Essa informação é obrigatória em todos os trabalhos que receberam apoio financeiro da Instituição. Agradecemos a compreensão. on 2018-04-19T18:09:14Z (GMT) / Submitted by Lucas Michelão Martins (lmichelaomartins@yahoo.com) on 2018-04-20T16:13:54Z No. of bitstreams: 2 tese doutorado lucas m martins.pdf: 4956302 bytes, checksum: b3d6b99c6519511aa67ed77e0edb7e9d (MD5) tese doutorado lucas m martins.pdf: 4956152 bytes, checksum: 2ea535fd613d58ddc831a51fa4390600 (MD5) / Approved for entry into archive by Minervina Teixeira Lopes null (vina_lopes@bauru.unesp.br) on 2018-04-23T18:31:59Z (GMT) No. of bitstreams: 1 martins_lm_dr_bauru.pdf: 4617641 bytes, checksum: ea0852f15d53498d1be6501963fc8c76 (MD5) / Made available in DSpace on 2018-04-23T18:31:59Z (GMT). No. of bitstreams: 1 martins_lm_dr_bauru.pdf: 4617641 bytes, checksum: ea0852f15d53498d1be6501963fc8c76 (MD5) Previous issue date: 2018-02-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Nesse trabalho nós apresentamos uma metodologia para a síntese dos derivados de tetra-aril-1,4-di-hidropirrol[3,2-b]pirroles através de uma reação multicomponente entre derivados de benzaldeído, derivados de anilina e a butano-2,3-diona promovida pelo pentacloreto de nióbio em condições brandas e com excelentes rendimentos, entre59 e 98% e com baixos tempos reacionais, de 20 a40 minutos. Uma comparação entre os resultados deste estudo e os encontrados na literatura para a síntese multicomponente de tetra-aril-1,4-di-hidropirrol[3,2-b]pirroles promovida por ácidos de Lewis também fez parte deste trabalho, e pudemos concluir que o pentacloreto de nióbio é muito eficiente nessa síntese, já que permite um maior rendimento em menor tempo reacional que os outros ácidos. Também apresentamos a caracterização óptica dos produtos sintetizados, com espectroscopia de absorção na região do UV-Vis e de fluorescência, onde observamos que os compostos sintetizados apresentaram valores comparáveis aos tieno[3,2-b]tiofenos e aos indolo[3,2-b]indoles, ambos sendo compostos que apresentam aplicações em dispositivos eletrônicos orgânicos. / In this work we report a method for the synthesis of tetraaryl-1,4-dihydropyrrolo-[3,2-b]pyrroles derivatives through a multicomponent reaction between benzaldehyde derivatives, aniline derivatives and butane-2,3-dione promoted by niobium pentachloride, in mild conditions with excellent yields, between 59 and 98% and low reaction times, from 20 to 40minutes. A comparison between our results and the ones found in the literature for the synthesis of tetraaryl-1,4-dihydropyrrolo-[3,2-b]pyrroles derivatives using different Lewis acids was also in the scope of this work, and we could conclude that niobium pentachloride is very efficient for these synthesis, since it gives better yields in lower time. We also show the optical characterization of the synthesized products, with UV-vis and fluorescence spectroscopy, where we could observe that the synthesized compounds presented values comparable with thieno[3,2-b]thiophenes and indolo[3,2-b]indoles, both having applications in organic electronic devices. / FAPESP 16/01599-1

No capítulo 1 apresentamos uma síntese eficiente de compostos 5-organoteluro-1H- 1,2,3-triazóis realizada via reação de cicloadição [3+2] entre azidas orgânicas e alquinos substituídos com organotelúrio. Além disso, os 5-organoteluro-1H-1,2,3-triazóis foram funcionalizados na posição 5 do anel triazólico por reação de acoplamento cruzado de Sonogashira. A regioquímica dos produtos de cicloadição foram descritas com base em experimentos de RMN, cálculos teóricos e cristalografia de raio-x. Apresentamos uma proposta mecanística para a cicloadição mediada por cobre, baseada em experimentos de espectrometria de massas de alta resolução. No capítulo 2, investigamos a eficiência de reações one-pot com indol, cloreto de oxalila e diferentes nucleófilos para obtermos derivados do indol-3-glioxila em condições adequadas. Do mesmo modo, envolvendo a adição de azidas orgânicas, levando à síntese de indol-3-glioxil-1,2,3-triazóis, os produtos foram obtidos com rendimentos que variaram de 59 a 85%. / In chapter 1 we present an efficient synthesis of 5-organotelluro-1H-1,2,3-triazole compounds that was accomplished via the [3+2]-cycloaddition reaction of organoazides and organotelluro alkynes. Additionally, 5-organotelluro-1H-1,2,3-triazoles were readily functionalized at the 5-position via the Sonogashira cross-coupling reaction, leading to highly functionalised triazoles. The regiochemistry of the products was assessed by bidimensional NMR experiments, theoretical calculations and x-ray crystallography. We presented a mechanistic proposal for the cycloaddition mediated by copper, based on high resolution mass spectrometry experiments. In chapter 2 we investigated a general and efficient reaction of indole with oxalyl chloride and nucleophiles providing indole-3-glyoxyl derivatives which has been developed in mild conditions. In the same fashion, the other reaction involved the addition of organic azides leading to the synthesis of indole-3-glyoxyl-1,2,3-triazoles, which proceeds smoothly generating the products in moderate to high yields.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2017-12-18T12:04:06Z No. of bitstreams: 2 Tese - Cameron Capeletti da Silva - 2017.pdf: 3293032 bytes, checksum: 714ecd70f3ac6d81018c08280d885007 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-12-18T12:04:37Z (GMT) No. of bitstreams: 2 Tese - Cameron Capeletti da Silva - 2017.pdf: 3293032 bytes, checksum: 714ecd70f3ac6d81018c08280d885007 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-12-18T12:04:37Z (GMT). No. of bitstreams: 2 Tese - Cameron Capeletti da Silva - 2017.pdf: 3293032 bytes, checksum: 714ecd70f3ac6d81018c08280d885007 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-12-13 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / A branch of lamivudine crystal engineering deals with its protonable pyrimidine-based nitrogen being a recipe of crystallization with acids. In this context and in relation to the drug lamivudine, ten new crystalline phases were prepared and their crystal structures were elucidated by single crystal X-ray diffraction. In addition, two of them were also characterized by infrared spectroscopy (IR) and other three were characterized by TG and DSC thermal analysis. Thus, this study shows an interesting example of chiral recognition even without chiral resolution. Lamivudine (R)-mandelate and (S)-mandelic acid cocrystal of lamivudine (R)-mandelate trihydrate showed the enantiopreference between lamivudine cation and the (R)-mandelandelate anion in both salt and cocrystal of salt phases through the robust synthon 2-aminopyridine-carboxylate. The present study shows how two solid forms of lamivudine with mandelic acid were used as a model to distinguish between the nature of a salt or cocrystal of salt. This happened because specific information obtained from IR spectra allowed the identification of ionized and neutral forms of mandelic acid directly in the spectrum of the cocrystal of salt. Furthermore, the formation of crystalline forms of lamivudine resembling a DNA structure was investigated due to its great structural value. After crystallization experiments three crystalline structures of lamivudine that mimics DNA structure were obtained and named as lamivudine duplex IV, V and VI, respectively. In the duplex IV of lamivudine the counterions are responsible for opening the two strands due to their hydrogen bonding pattern. The theoretical approach has shown that there is not an energetic tendency regarding the formation of lamivudine duplex with aliphatic organic acids or lamivudinium salts with aromatic acid. Thus, the preference of lamivudine in the assembly of double-helix structures with aliphatic organic acids rather than aromatic acids has been rationalized based on the amount of acid used during the synthesis. In addition, four other salts were also prepared by crystallizing lamivudine with the L-tartaric, sulfuric and perchloric acids, where the two-point synthon described by the graph set R22(8) prevailed. On the other hand, in the structure of lamivudine perchlorate monohydrate neither the two-point synthon nor the three-point one was observed. Finally, the first anhydrous polymorph of lamivudine was reported. This new polymorphic phase of lamivudine is anhydrous as well as form II. In addition to being a new solid phase of alleged commercial interest, the polymorphic form IV of lamivudine also reinforces the importance of performing an extensive screening of the crystallization conditions of new crystalline modifications of active pharmaceutical ingredients. / Um ramo da engenharia de cristais de lamivudina lida com sua base nitrogenada pirimidina, a qual pode ser protonada, sendo assim um alvo de cristalização com ácidos. Nesse contexto, e com relação ao fármaco lamivudina, dez novas fases cristalinas foram preparadas e suas estruturas cristalinas foram elucidadas por difração de raios X por monocristal. Além disso, duas delas também foram caracterizadas por espectroscopia no infravermelho (IV) e outras três foram caracterizadas termicamente por TG e DSC. Desse modo, esse estudo mostra o interessante exemplo de reconhecimento quiral mesmo sem resolução quiral. O (R)-mandelato de lamivudina e o co-cristal (S)-mandélico de (R)-mandelato de lamivudina trihidratado revelaram a enantiopreferência da conexão entre o cátion (lamivudina)+ e o ânion (R)-mandelato- em ambas fases de sal e co-cristal de sal através do sínton robusto de dois pontos 2-aminopiridina-carboxilato. O presente estudo mostra que as duas formas sólidas de lamivudina com ácido mandélico foram utilizadas como modelo para distinguir entre a natureza de um co-cristal de sal e de um sal. Isso porque informações específicas obtidas dos espectros de IV tornaram possível identificar ambas as formas ionizadas e neutra do ácido mandélico diretamente no espectro do co-cristal de sal. Ainda, investigou-se a formação de formas cristalinas de lamivudina que se assemelham a estrutura de DNA devido a seu grande valor estrutural. Após os experimentos de cristalização foram obtidas três estruturas cristalinas de lamivudina semelhantes a estrutura de DNA denominadas de dupla hélice de lamivudina IV, V e VI. Na dupla hélice de lamivudina IV os contra-íons são responsáveis pela abertura da dupla fita devido ao seu padrão de ligação de hidrogênio. A abordagem teórica mostrou que não há uma tendência energética com respeito a formação de duplex de lamivudina com ácidos orgânicos alifáticos ou de sais de lamivudina com ácidos aromáticos. Desse modo, a preferência da lamivudina em montar estruturas cristalinas de dupla hélice com ácidos orgânicos alifáticos ao invés de ácidos aromáticos foi racionalizada com base na quantidade de ácido usada durante a síntese. Além disso, também foram preparados outros quatro sais ao cristalizar lamivudina com os ácidos L-tartárico, sulfúrico e perclórico, onde o sínton de dois pontos descrito pelo conjunto gráfico R22(8) prevaleceu. Por outro lado, na estrutura do perclorato de lamivudina monohidratado nem o sínton de dois pontos e nem o de três pontos foram observados. Por fim, o primeiro polimorfo anidro de lamivudina foi reportado. Essa nova fase polimórfica de lamivudina é anidra assim como a forma II. Além de ser uma nova fase sólida de suposto interesse comercial, a forma polimórfica IV de lamivudina também reforça a importância de se realizar uma varredura extensiva das condições de cristalização de novas modificações cristalinas de insumos farmacêuticos ativos.

Eskers are long winding ridges that originate from gravel that has travelled in meltwater streams in glaciers. At the study site, Virttaankangas plane in southwest Finland, there are esker structures covered by sediments. One reason why it is important to study eskers is because they are used for purifying drinking water. The data used in the study were collected during a seismic survey in July 2014. During the survey a controlled source created seismic waves that travelled down through the earth and then reflected back up again. By detecting the travel time of the waves and estimating the velocity of the geologic layers, the depth to the reflecting structures could be calculated. There are two types of waves that travel through the body of the earth, pressure waves (P-waves) and shear waves (S-waves). In a previous study (Maries et al., 2017) P-wave data from the same survey have been analyzed, so this work focuses on S-wave data but also compares the result from the two. Some structures related to eskers were identifiable, such as fractures in the bedrock from the pressure of the main esker core. By comparing S- and P-wave results it was possible to see hints of the arched esker cores and esker fan lobes. Overall the result confirmed the model that was achieved of the profile in the previous study. The location of the bedrock both matched with the previous study, and added information about its orientation. An additional goal was to demonstrate the insensitivity of S-waves to water content by showing that if there was a water table reflection in the P-wave data, this reflection was missing in the S-wave data. The results showed water table reflections in the P-wave data, but there were no distinguishable water table reflections with appropriate velocity for S-waves in the S-wave data. / Rullstensåsar definieras som långa åsar med storlekssorterat grus som avlagrats av smältvattenströmmar i glaciärer. Vid undersökningsplatsen, Virttaankangasheden i sydvästra Finland, finns rullstensåsstrukturer som är begravda under sediment. En anledning till varför det är viktigt att undersöka rullstensåsar är att de används för filtrering vid framställning av dricksvatten. De data som användes i denna studie inhämtades under en seismisk undersökning i juli 2014. Undersökningen gick till på så vis att en kontrollerad källa skapade seismiska vågor som färdades ner i jorden för att sedan reflekteras tillbaka upp mot ytan. Genom att notera tiden det tog för vågorna att färdas, samt uppskatta hastigheten i de geologiska lagren, kunde djupet till de reflekterande strukturerna beräknas. Det finns två sorters vågor som kan färdas genom jorden, tryckvågor (P-vågor) och skjuvvågor (S-vågor). I en tidigare studie (Maries et al., 2017) analyserades P-vågsdata från samma seismiska undersökning, så detta arbete fokuserar på S-vågsdata men jämför också resultaten av båda två. Vissa strukturer kopplade till rullstensåsar kunde identifieras, så som sprickor i begrgrunden från trycket av den största rullstensåsen. Genom att jämföra resultat från S- och P-vågor kunde man se reflektioner från rullstensåsar och sediment. Sammantaget bekräftade resultatet den modell över profilen som framtagits i den tidigare studien. Berggrundens läge stämde överens med den förra studien och tillförde ny information om dess orientering. Utöver detta försökte man också demonstrera S-vågors okänslighet för vatten genom att visa att om det fanns reflektioner från grundvattenytan i P-vågsdatan så skulle de reflektionerna inte synas i S-vågsdatan. I P-vågsdatan visade det sig att det fanns grundvattenreflektioner, men det gick inte att urskilja några liknande reflektioner i S-vågsdatan.

Les “alliages à haute entropie (de mélange)” (AHE) sont une nouvelle famille de matériaux prometteurs. Ils sont caractérisés par la formation d'une solution solide à 5 éléments (en proportions équiatomiques) de structure cristalline simple. Dans cette thèse, la composition cubique centrée TiZrNbHfTa est étudiée, proposant une caractérisation en profondeur d’un alliage considéré « de référence » dans la famille des AHE réfractaires.Tout d'abord, la microstructure et la structure de l’alliage (dans son état brut de coulée ou recristallisé) sont étudiées. L’environnement local de sous-systèmes de TiZrNbHfTa est analysé par EXAFS. Le traitement des données est effectué par une double approche d’affinement EXAFS et de simulation Reverse Monte-Carlo couplée à une approche d’algorithme génétique. Un mélange quasi-parfait des différents éléments est obtenu à l’échelle locale et la distribution de distance des premiers voisins devient moins bien définie sous l’effet de l’augmentation des différences entre rayons atomiques.Ensuite, l’impact de la solution solide concentrée sur les propriétés mécaniques et les mécanismes de déformation de l’alliage est étudié. Des essais mécaniques spécifiques sont effectués, conduisant à l’obtention des volumes d’activation et à la partition de la contrainte d’écoulement. Une étude MET complémentaire permet d'analyser les microstructures de déformation. Une très haute limite d’élasticité est obtenue, mais la force de friction de Peierls contrôle de manière classique la déformation de cet alliage à la température ambiante, ce qui conduit à un taux d’écrouissage limité. Une nouvelle approche visant à augmenter cette propriété est finalement proposée / High entropy alloys (HEA) are a new promising type of materials. Breaking with the traditional alloying concepts, solid solution(s) based on 5 elements in equiatomic concentration with simple crystal structures are obtained. In this study, the equiatomic composition TiZrNbHfTa is investigated, in order to provide an in-depth characterization of a “reference” body centered cubic refractory HEA.First, the microstructure and structure of the alloy are studied. Thermomechanical treatments procedures are established to access recrystallized microstructures. The local environment is studied by EXAFS in sub-components of the TiZrNbHfTa system. The double approach used, based on EXAFS fit and reverse Monte-Carlo coupled with evolutionary algorithm allowed to quantify both the mixing of the elements at the atomic scale and the lattice distortion. For all the investigated compositions, good mixing is achieved, and the distance distribution of first nearest neighbors becomes less precise with increasing atomic size mismatch.Then, the impact of such concentrated multi-element solid solution on the mechanical properties and the deformation mechanism of the material is investigated by specific tests. The activation volumes and the flow stress partition are extracted. The mechanical results are coupled with a TEM study. This part evidences that the alloy displays an impressive yield strength. However, the high lattice friction controlling the dislocation glide does not differ from classical bcc structures, leading to a rather low work hardening. A new design approach aiming at increasing the work-hardening in such materials is finally proposed, and a proof of concept is given

The studies on cocrystals and salts presented in the the chapters clearly bring out the influence of intermolecular interactions as the main evaluators of the cocrystal-salt regime. The observations made in Chapter 2 indicate that in case if the cocrystal formation is through hydrogen bonds the location of the proton decides the nature of the complex in the energy landscape. The observation that the coformer controls the topology of intermolecular space as demonstrated in Chapter 3 provides insights into the importance of directionality rather than strength of intermolecular interactions. Indeed halogen bonding in cocrystals gain importance in this context.

La protection des salariés travaillant dans une atmosphère chargée en composés organiques volatils (COV) peut être assurée par l’utilisation d’une cartouche filtrante en charbon actif. Doté d’une structure microporeuse, le charbon actif possède une très haute surface spécifique favorable à la rétention de constituants toxiques par des phénomènes d’adsorption. Prévoir le temps de fonctionnement d’un appareil de protection respiratoire constitue un des objectifs de l’Institut National de Recherche et de Sécurité. Mondialement utilisé par les organismes préventeurs, le modèle dynamique de Wheeler Jonas muni d’un modèle d’équilibre adéquat fournit des temps de claquage de cartouches exposées à un débit constant d’air sec pollué par un COV. Même si ce modèle a subi des améliorations ces dernières années, il ne permet pas de décrire correctement le comportement des cartouches en présence de copolluant ou d’humidité. Dans le présent travail, un modèle numérique permet la description de l’adsorption dynamique des COV seuls et en mélange sur un lit fixe de charbon actif. L’adsorption dynamique de l’eau a également été étudiée et modélisée. Cette étude particulière nous a permis de comprendre l’influence de l’eau sur la performance de la cartouche respiratoire. De nombreux fronts de percée ont été réalisés afin d’acquérir des informations indispensables à la description de l’équilibre d’adsorption et du transfert de matière en milieu poreux. Ces expériences ont permis d’implémenter des données pour la modélisation de l’adsorption dynamique multiconstituante. Cette dernière inclut l’adsorption binaire COV-COV et l’adsorption d’un COV en présence d’eau. Le travail effectué a permis de proposer des solutions adaptées à la complexité du sujet / Activated carbon is the sorbent used in respirator cartridges to purify breathing air by adsorbing organic vapors. Owing to an important microporous structure, the activated charcoal features a high specific area efficient to capture toxic compounds by adsorption. Predicting service life time of respirator cartridges to protect users working in a polluted atmosphere is a mission of the Institut National de Recherche et de Sécurité. The Wheeler-Jonas approach, provided with a suitable equilibrium model, is a worldwide used equation to get service life times of respirator cartridges exposed to a constant flow of dry air polluted by a single volatile organic compound (VOC). While this model has been improved in recent years, it does not adequately describe the behavior of the cartridges in the presence of moisture or copolluant. The present study aims to build a numerical model to describe dynamic adsorption of single volatile organic compounds and mixtures with or without relative humidity in the air. Single water vapor adsorption has been modeled on a coaled fixed-bed, it provides a useful description of water adsorption on activated carbon and the impact of water on the service life time of a respirator cartridge. Numerous experiments have been realized to get equilibrium data of single VOCs and mass transfer constants to describe diffusion of adsorbates through micropores. Indeed, these data have been implemented in the model to describe adsorption of mixtures. Additional experiments have been realized to study coadsorption of organic vapors and dynamic adsorption of a single VOC in presence of humidity. The results are compared with simulations to appreciate the pertinence of the model. The present work provides solutions tailored to the complexity of the subject

La maladie d'Alzheimer est la pathologie neurodégénérative la plus courante affectant les personnes âgées. Cette neuropathologie se caractérise par une étiologie complexe dont le déficit en acétylcholine, les plaques amyloïdes, les dégénérescences neurofibrillaires ou le stress oxydant en sont les principaux acteurs.Au cours de cette thèse, nous nous sommes intéressés à l'application des réactions multicomposants de Ugi et de Passerini, pour la synthèse de nouveaux adduits multi-cibles basées sur différents motifs antioxydants et anticholinestérasiques. Ces réactions permettent d'accéder à une vaste diversité chimique en une étape, ce qui les rend adaptées pour la synthèse rapide de molécules ayant plusieurs pharmacophores d'intérêt et ciblant ainsi différentes cause étiologiques de la maladie d'Alzheimer.Au total, 56 composés finaux, répartis dans cinq séries, ont été synthétisés :les alpha-acylaminocarboxamides prototypes (série A)les hybrides tacrine-acide férulique (série B)les hétérotrimères tacrine-mélatonine-acides antioxydant (série C)> les hybrides donépézil-acide férulique (série D)^ les dérivés chromone (série E)Toutes les séries ont été évaluées pour leur capacité à inhiber les enzymes cholinestérases et leur pouvoir antioxydant. L'hépatotoxicité des séries B et C. portant un motif tacrine, a été évaluée sur les cellules HepG2. Par ailleurs, l'étude de la série B a été complétée par d'autres tests pharmacologiques, physico-chimiques et toxicologiques.Ces différents travaux démontrent et valident l'utilisation des réactions de Ugi et de Passerini dans le développement de molécules multi-cibles pour le traitement potentiel de la maladie d'Alzheimer. / Alzheimer's disease (AD) is thé most common type of dementia affecting elderly people. This neuropathology is characterized by a highiy complex and intricated etiology including cholinergic déficit, amyloid deposits, neurofibrillary tangles and oxidative stress.During this thesis, we sought to apply Ugi and Passerini multicomponent reactions for thé synthesis of new multi-target adducts based on différent antioxidant and anticholinergic scaffolds.Thèse réactions provides access to a broad range of chemical diversity in a one-pot fashion, which makes them suitable for thé expeditious synthesis of molécules having several pharmacophores of interest and hitting différent targets related to thé multifaceted etiology of Alzheimer's disease.A total of 56 final compounds, spread over 5 séries, hâve been synthesized:alpha-acylaminocarboxamides prototypes (A séries)tacrine-ferulic acid hybrids (B séries)tacrine-melatonin-antioxydant acids heterotrimers (C séries)donepezil-ferulic acid hybrids (D séries)Chromone derivatives (E séries)Ail thé séries were tested for their ability to inhibit thé cholinesterases enzymes and for their antioxidant power. Hepatotoxicity of thé B and C séries, bearing a tacrine fragment, was evaluated on HepG2 cells. Moreover, thé study of thé B séries was supplemented by further pharmacological, physicochemical and toxicological tests (NMR conformational study, neuroprotection on SH-SY5Y cells. self-induced Abetai.42 peptide aggregation inhibition, docking ADMET).Such work demonstrated and validated thé use of Ugi and Passerini reactions for thé development of new multi-target directed molécules for thé potential treatment of AD.

The goal of this project is design of manufacturing technology for door elastomer grommet in a series of 400 000 units per year. As a proposed solution of manufacturing technology has been chosen multicomponent injection moulding. Appropriate thermoplastic elastomer and polyamide was chosen based on the knowledge gained in theoretical study of materials and technologies elaborated in the second part of the project. Moreover, the shape of the door grommnet was redesigned in accordance with the chosen technology. Working machine was chosen from manufacturer Arburg, model Allrounder 630S in a two-shot design, complemented by the index unit. A cost of production of one piece of the door grommet was determined in an economic evaluation. This cost was compared with current cost of production and new technology reducing manufacturing costs of one series by 25%.