L’élaboration de nouveaux complexes métalliques possédant des propriétés physiquesintéressantes et multiples est un cadre de recherche très actif ces dernières années.Parallèlement, les molécules dérivées d’énaminones fluoroalkylées sont modifiables à souhaitet sont reconnues pour leur utilisation en tant que ligand. Ces synthons se révèlent alorsparticulièrement adaptés pour élaborer des complexes variés via des techniques de chimie decoordination.Dans ce contexte, un programme de recherche a été récemment initié et consiste en lasynthèse de ligands de type énaminone trifluorométhylée bi, tri et tétradentes pouvant êtremodifiés en fonction des propriétés ciblées. Ainsi, la substitution du motif par des unités detype azobenzène, anthracène, tétrathiafulvalène, 1,2,3-triazole… a permis de révéler pourceux-ci une photosensibilité, une activité redox ou encore une bioactivité.De plus, au travers de leur différence de denticité, ces ligands conduisent à descomplexes métalliques de nucléarité contrôlée. Ainsi ce sont des composés mononucléairesd’une part et polynucléaires d’autre part qui sont obtenus pour lesquels une propriété redox etmagnétique est observée respectivement.Ainsi, le projet est dédié à l’élaboration d’objets moléculaires innovants etpolyfonctionnels au sein desquels cohabitent une propriété portée par le ligand organiquestructurant et une propriété issue du coeur métallique central. / The synthesis of new metal hybrid inorganic-organic metallic complexes with severalinteresting physical properties is an area of intense research. On another hand, fluoroalkylatedenaminone derivatives have been scarcely employed as useful ligands although these organicmolecules can offer very rich coordination chemistry with broad applications in materialsscience.In this context, a research program was recently initiated, dedicated to thedevelopment of bi, tri, and tetradentate trifluoromethylated enaminone ligands that can bemodified according to the targeted properties. Indeed, a photosensitivity, a redox property or abioactivity was found for these ligands with the introduction of units such as azobenzene,anthracene, tetrathiafulvalene, 1,2,3-triazole …In addition, according to their different denticity, these ligands can afford somemetallic complexes with a controlled nuclearity. In one hand, mononuclear complexes areobtained with a redox property and in antoher hand some polynuclear complexes withinteresting magnetic behaviours.The research program is thus dedicated to the elaboration of innovating andpolyfunctionnal molecular objects in which a property arising from the organic structuringligand coexists with the property of the metallic center.

Design and development of novel one-step reactions that produce nitrogen-containing scaffolds is an invaluable area of chemistry due to the abundance of these moieties in natural products and biologically active molecules. Discovering novel methods using uncommon substrates and rare earth metals to access these significant scaffolds present a challenge. Over the course of my doctoral studies, I have designed, developed and optimized novel reactions by using rarely known substrates and rare earth metals that have afforded important nitrogen-containing scaffolds. The products obtained allow access to otherwise long-to-synthesize molecules and expeditious construction of biologically active molecules.

The use of enamines continues to be an important tool in organic syntheses as both a catalyst and reactant. The addition of metal catalysts coupled with enamine catalysis has generated many reactions that normally would not occur separately. However, catalysts' incompatibility is an issue that we wish to solve allowing new chemistry to occur without hindrance. The use of enamines has continued to be a well-studied area of organic chemistry, but the field is ripe for different types of enamines to gain the spotlight. Enaminones are enamines with both nucleophilic and electrophilic properties. They allow reactions that are normally not possible with enamines to become obtainable. Chapter 1 is a brief introduction on enamines and the reason they gained so much attention. Then ends with enaminones and what makes them interesting reactants. Chapter 2 described a new synthesis for the tricyclic synthesis of chromanes using a novel bifunctional catalyst system of enamine-metal Lewis acid giving great yields (up to 87 %yield) and excellent stereoselectivity (up to 99 % ee). Chapter 3 covered new reactions for ring-open cyclopropane (up to 94% yield), tetrahydroquinolinones (up to 84% yield) and enantiospecific tetrahydroquinolinones (up to 84% yield and 97% ee) using α-enaminone and donor-acceptor cyclopropanes. Finally, Chapter 4 focused a new method for synthesizing benzobicyclo[3.2.1]octanes with an added sterically bulky quaternary center and imine functionalization giving yields between 36-73% yield using α-enaminone with alkylidene malonates.

L'élaboration de nouveaux complexes métalliques possédant des propriétés physiquesintéressantes et multiples est un cadre de recherche très actif ces dernières années.Parallèlement, les molécules dérivées d'énaminones fluoroalkylées sont modifiables à souhaitet sont reconnues pour leur utilisation en tant que ligand. Ces synthons se révèlent alorsparticulièrement adaptés pour élaborer des complexes variés via des techniques de chimie decoordination.Dans ce contexte, un programme de recherche a été récemment initié et consiste en lasynthèse de ligands de type énaminone trifluorométhylée bi, tri et tétradentes pouvant êtremodifiés en fonction des propriétés ciblées. Ainsi, la substitution du motif par des unités detype azobenzène, anthracène, tétrathiafulvalène, 1,2,3-triazole... a permis de révéler pourceux-ci une photosensibilité, une activité redox ou encore une bioactivité.De plus, au travers de leur différence de denticité, ces ligands conduisent à descomplexes métalliques de nucléarité contrôlée. Ainsi ce sont des composés mononucléairesd'une part et polynucléaires d'autre part qui sont obtenus pour lesquels une propriété redox etmagnétique est observée respectivement.Ainsi, le projet est dédié à l'élaboration d'objets moléculaires innovants etpolyfonctionnels au sein desquels cohabitent une propriété portée par le ligand organiquestructurant et une propriété issue du coeur métallique central.

This thesis describes studies directed towards development of novel antiadhesive agents, with particular emphasis on compounds that prevent attachment of bacteria to a host-cell. Three different proteins involved in the assembly or function of adhesive pili in uropathogenic Escherichia coli have been targeted either by rational structure based design or statistical molecular methods. A library of substituted galabiose (Galα1-4Gal) derivatives was screened for binding to the E. coli adhesin PapG in an assay based on surface plasmon resonance, and for inhibition of Streptococcus suis adhesins PN and PO in a hemagglutination assay. The results were used to generate QSAR models which had good predictive powers and provided further insight in the structural requirements needed for high affinity binding. 2-pyridones and amino acid derivatives were modelled into the binding site of chaperones involved in pilus assembly in E. coli and a heuristic method, VALIDATE, was used for affinity prediction. The affinity of the compounds for the chaperones PapD and FimC were assessed in assays based on surface plasmon resonance and relaxation-edited NMR spectroscopy. Their ability to disrupt chaperone/subunit complexes was investigated in vitro through a FPLC assay and their capacity to inhibit pilus formation in vivo was determined via hemagglutination and confirmed with atomic force microscopy. Statistical molecular design was used to design a diverse peptide library targeting pili subunits, and an ELISA was developed to investigate the ability of the peptides to inhibit chaperone/subunit complexation. The resulting QSAR model provided extensive information regarding binding of the peptides to the subunits. Because the peptides were suggested to bind in an extended β-strand formation, β-strand mimetics consisting of oligomeric enaminones were designed. Finally, new methods to synthesize enaminone building blocks were developed using microwave assisted chemistry. The projects described have generated compounds that besides their value as leads for developing novel antibacterial agents, also constitute new chemical tools to study the mechanisms underlying bacterial virulence.

[pt] Por ser uma doença genética, resultado de uma mutação em um gene específico, que gera proteínas (CFTR) defeituosas, a Fibrose Cística é uma patologia difícil de ser tratada. Os custos para os tratamentos atualmente disponíveis são altos, sem os quais, porém, a gravidade da doença tende a crescer ainda mais. Por esse motivo, novos tratamentos farmacológicos vêm surgindo, como o Trikafta (marca registrada), uma combinação tripla de fármacos com ação sinérgica (elexacaftor, ivacaftor e tezacaftor). Porém, esse medicamento ainda não é disponível no Brasil e o acesso aos tratamentos, em geral, são onerosos. Sendo assim, este trabalho visa a síntese de compostos 1,2,3-triazóis, com possível atividade biológica frente a proteína CFTR, sugerida por ancoragem molecular. Este trabalho também visa selecionar as melhores moléculas quanto aos perfis farmacocinéticos e toxicológicos, avaliados por ferramentas computacionais como swissADME e VirtualToxLab, respectivamente. Dessa forma, a estratégia sintética para a obtenção dos compostos consiste em duas etapas sintéticas. A primeira, envolve a síntese da enaminona – (E)-3-(dimetilamino)acrilaldeido (3a-d) – por organocatálise, a partir de L-prolina e DMA-DMF (1,1-dimetoxi-N,N-dimetillmetanamina) (1). A segunda etapa inclui a reação de cicloadição 1,3-dipolar onpot entre as azidas (5a-h) e as enaminonas previamente obtidas. Assim, foi possível obter 1,2,3-triazóis 1,4-substituídos (6a-k), com rendimentos de 5 a 96 por cento. Dentre eles, a molécula 6k, N-(2-(1-(4-metoxifenil)-1H-1,2,3-triazol-4-carbonil)fenil)acetamida), destacou-se quanto aos perfis toxicológicos e também pelos resultados observados nos estudos de ancoragem molecular. Os espectros de RMN de 1H e 13C RMN confirmaram a obtenção das estruturas. / [en] Because it is a genetic disease, the result of a mutation in a specific gene, which generates defective proteins (CFTR), Cystic Fibrosis is a pathology that is difficult to be treated. The costs for currently available treatments are high, without which, however, the severity of the disease tends to increase even more. For this reason, new pharmacological treatments are emerging, such as Trikafta (trademark), a triple combination of drugs with synergistic action (elexacaftor, ivacaftor and tezacaftor). However, this drug is not yet available in Brazil and access to treatments, in general, is expensive. Therefore, this work aims at the synthesis of 1,2,3-triazole compounds, with possible biological activity against the CFTR protein, proposed by molecular anchoring. This work also aims to select the best molecules in terms of pharmacokinetic and toxicological profiles, evaluated by computational tools such as swissADME and VirtualToxpot, respectively. Thus, the synthetic strategy for obtaining the compounds consists of two synthetic steps. The first involves the synthesis of enaminone - (E)-3-(dimethylamino) acrylaldehyde (3a-d) - by organocatalysis, starting from L- proline and DMA-DMF (1,1-dimethoxy-N, N-dimethylmethanamine) (1). The second stage includes the 1,3-dipolar onpot cycloaddition reaction between the azides (5a-h) and the previously obtained enaminones. Thus, it was possible to obtain 1,4-substituted 1,2,3-triazoles (6a-k), with yields of 5 to 96 percent. Among them, the molecule 6k, N- (2- (1- (4-methoxyphenyl) -1H-1,2,3-triazol-4-carbonyl) phenyl) acetamide), stood out in terms of toxicological profiles and also by results observed in molecular anchorage studies. The 1H and 13C NMR NMR spectra confirmed the structures obtained.