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No / A novel, convenient, and high-yielding method has been developed for the preparation of heterocyclic N-oxides. The reaction uses the urea·hydrogen peroxide addition complex as a peroxide source for the in situ generation of trifluoroperacetic acid. The advantages of this method are easy handling of a stable, solid oxidant; high yields and simple removal of excess reagents and by-products.

Les interactions protéine - protéine sont au centre de nombreux processus biologiques, et représentent des cibles thérapeutiques pertinentes pour le traitement de certaines maladies. La conception de molécules antagonistes visant à inhiber ces interactions requiert la reconnaissance spécifique d’une des surfaces protéiques impliquées. Les foldamères de type oligoamides de quinoline constituent de bons candidats. Leur production et leur fonctionnalisation sont relativement aisées. Ils adoptent des structures hélicoïdales semblables à celles rencontrées dans les protéines. Grâce à différentes techniques biophysiques (CD, SPR, diffraction des rayons X), nous montrons que ces molécules sont aptes à reconnaître une surface protéique. Deux protéines cibles ont été choisies : l’interleukine 4 et l’anhydrase carbonique humaine II.La stratégie retenue dans ce travail (ancrage du foldamère à la protéine via un bras espaceur) nous a permis d’obtenir des informations structurales sur les interactions foldamère – protéine avant toute optimisation de ces interactions. La première structure 3D d’un complexe foldamère de quinoline complexée à une protéine est décrite. / Protein-protein interactions are a central issue in biological processes and represent relevant therapeutic targets for the treatment of diseases. The design of antagonistic molecules directed towards the disruption of these interactions requires the specific recognition of protein surfaces. Quinoline oligoamide foldamers present all the properties to reach that point. They are easily synthesized and fold into helices (similar to α helices) which can be decorated. Thanks to biophysical studies (CD, SPR, RX diffraction), we demonstrate that these molecules are able to recognize protein surfaces. Two proteins have been studied: the human interleukin 4 and the human carbonic anhydrase II.The applied strategy (keeping the foldamer close to the protein surface via a linker) allowed us to gather structural information about foldamer protein interactions before any strong binding is established. The first crystal structure between a protein and an aromatic amide foldamer is reported.

Une multitude de composés organiques présente une structure bicyclique azotée insaturée.Parmi ceux-ci, le motif pyridine-[b]-bicyclique est extrêmement fréquent, et se compose d’unepyridine accolée à un autre cycle aromatique. Cependant, les méthodes de synthèse de cescomposés sont aujourd’hui encore trop spécifiques. Les conditions réactionnelles ne sont pastoujours utilisables, ou ne permettent pas de préparer certains produits spécifiques. Afin des’affranchir de ces limitations, une nouvelle méthode de construction du cycle pyridine à partirdu motif ß–aminoacrylonitrile est proposée dans ce manuscrit, utilisant un alcène activé par unmotif trichlorométhyle.Outre la préparation de ces pyridines-[b]-bicycliques, la réactivité des pyrazolo[3,4-b]pyridines a été étudiée. Des réactions de fonctionnalisation de fin de synthèse ont étédéveloppées, qui exploitent des procédures basées sur la chimie du palladium. Trois positionsdes pyrazolopyridines ont pu être arylées, permettant d’accéder à de nouveaux composés / Bicyclic unsaturated structures containing one or more nitrogen atom appear in a widerange of organic compounds. In particular, the [b]-fused pyridine is a frequent structural motif,with striking biological activities. However, there is still a lack for general methods, withrespect to the reaction conditions or the scope. In order to override these limitations, a newsynthetic procedure for preparation of the pyridine ring starting from ß–aminoacrylonitrile isproposed. This procedure relies on a trichloromethyl-activated alkene.The reactivity of pyrazolo[3,4-b]pyridine, a subclass of [b]-fused pyridine, have beeninvestigated. Some late-stage functionnalization have been developped, relying on palladiumcatalyzed chemistry. Three positions of the pyrazolopyridine core have been arylated, thusgiving access to new structures

Ce travail présente la synthèse, la caractérisation et l’utilisation (transfert électronique photo-induit) de foldamères de taille nanométriques constitués d’unité quinolines. Grâce a une stratégie de synthèse de doublement de segment une grande variété d’oligomères (jusqu’à 96 unités) ont pu être préparé à partir du synthon 8 aminoquinoline-2-carboxylate.Leurs propriétés dynamiques de ces objets ont été étudiées en solution et en phase gazeuse. La spectrométrie de masse de mobilité ionique a permis de déterminer leur conformation en phase gazeuse. Les expériences de RMN DOSY et d’anisotropie de Fluorescence ont permis de déterminer leurs propriétés de diffusion (transrationnelle et rotationnelle). Ces résultats ont révélés qui ces foldamères sont rigides et que leur architecture hélicoïdale est conservée.Le transport électronique photo-induit à travers ces foldamères de taille nanométrique ont été étudié et le mécanisme de transfert ainsi que son efficacité ont été déterminé pour une série de composés de tailles variables. / Herein, synthesis, characterization and application (photoinduced electron transport) of nanosized quinoline-based foldamers have been explored. With double segment strategy, a variety of helical nanosized foldamers (up to 96 quinoline units) were successfully prepared based on 8-aminoquinoline-2-carboxylic acid monomer.The dynamic properties in gas phase and solution were investigated. Ion mobility mass spectrometry afforded access to the conformation state of foldamers ingas phase; DOSY and fluorescence anisotropy assessed the diffusion (translational and rotational, respectively) of foldamers in solution. All of these techniques revealed that quinoline-based foldamers are rigid and that helical conformation is conserved. Photoinduced electron transport through nanosized foldamer was also studied and the mechanism and the transport ratios were revealed.

Ce manuscrit détaille la stratégie utilisée par nos laboratoires pour identifier de nouvelles molécules neuroprotectrices pour le traitement curatif de la maladie de Parkinson (MP). La MP est une maladie neurodégénérative caractérisée par des symptômes moteurs invalidants qui résultent de la dégénérescence des neurones dopaminergiques (DA) des noyaux gris centraux. Précédemment, nos laboratoires ont synthétisé et identifié au cours d’un criblage 3 molécules chefs de file qui possèdent un effet neurotrophique sur les neurones DA embryonnaires. Des études préliminaires d’ADMEtox nous ont permis de sélectionner la molécule SF41, un dérivé 6-aminoquinoxaline, pour une première évaluation de l’effet neuroprotecteur in vivo de nos molécules. En effet, cette molécule est bien tolérée chez l’animal et, administrée par voie orale, elle est capable de traverser la BHE. SF41 a montré un faible effet protecteur vis-à-vis des fibres DA dans un modèle animal de la MP. Dans le but d’augmenter l’activité neurotrophique de cette molécule, une 50ène de dérivés de seconde génération ont été synthètisés et criblés in vitro dans un modèle de mort spontanée des neurones DA. Ce criblage nous a permis d’identifier 5 molécules lead plus puisssantes et efficaces que SF41. Ces molécules, qui possédent les mêmes propriétés physico-chimiques que SF41, pourraient également atteindre le système nerveux central et ainsi conduire à un effet neuroprotecteur marqué dans un modèle animal de la MP. De plus, ces molécules possèdent un profil pharmacologique intéressant car elles sont capables d’empêcher la mise en place de mécanismes qui peuvent potentiellement contribuer à la mort des neurones DA dans la MP (stress oxydant, stress médié par les astrocytes, dyshoméostasie calcique, stress médié par la diminution en facteur trophique…). Une étude préliminaire avec la molécule PAQ, l’une de ces 5 molécules, a permis d’obtenir un effet neuroprotecteur dans un modèle in vivo de la MP qui semble supérieur à celui de la molécule SF41. Ces résultats encourageants nous donnent bon espoir d’obtenir la preuve de concept de l’activité neuroprotectrice de nos dérivés 6-aminoquinoxaline. / This manuscript describes the strategy used by our laboratories to identify new neuroprotective molecules for the therapy of Parkinson disease (PD). PD is a neurodegenerative disease characterized by disabling motor symptoms resulting from the degeneration of dopaminergic (DA) neurons of the basal ganglia. Previously, our laboratories have synthesized and identified in a screening 3 lead compound which exhibited a neurotrophic effect on embryonic midbrain DA neurons. Preliminary ADMEtox studies allowed us to select the molecule SF41, a 6-aminoquinoxaline derivative, for a first in vivo evaluation of the neuroprotective effect of our molecules in an animal model of PD. Indeed, SF41 is well tolerated in animals and is able of crossing the BBB after oral treatment. SF41 showed a weak protective effect on DA fibers in an animal model of PD.In order to increase the neurotrophic activity of this molecule, around fifty second generation derivatives were synthesized and screened in vitro in a model of spontaneous death of DA neurons. This screening allowed us to identify five lead compounds more powerful and effective than SF41. These molecules, which possess the same physico-chemical properties that SF41, could also reach the central nervous system and lead to a marked neuroprotective effect in an animal model of PD. In addition, these molecules have an interesting pharmacological profile because they are able to prevent the establishment of mechanisms that can potentially contribute to the death of DA neurons in PD (oxidative stress, stress mediated by astrocytes, calcium dyshomeostasis, stress mediated by trophic factor deprivation...).A preliminary study with the molecule PAQ, one of these five molecules, yielded a neuroprotective effect in animal model of PD that seems higher than with SF41. These encouraging results give us hope to achieve proof of concept of the neuroprotective activity of our 6-aminoquinoxaline derivatives.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2018-07-27T18:43:45Z No. of bitstreams: 2 Dissertação - Maria Eugênia de Oliveira Ferreira - 2017.pdf: 2295850 bytes, checksum: 937ef23483ab6e46d51253d73c4e2ef2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-07-30T14:07:22Z (GMT) No. of bitstreams: 2 Dissertação - Maria Eugênia de Oliveira Ferreira - 2017.pdf: 2295850 bytes, checksum: 937ef23483ab6e46d51253d73c4e2ef2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-07-30T14:07:22Z (GMT). No. of bitstreams: 2 Dissertação - Maria Eugênia de Oliveira Ferreira - 2017.pdf: 2295850 bytes, checksum: 937ef23483ab6e46d51253d73c4e2ef2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-06-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Heavy petroleum fractions, especially the vacuum residue, concentrate the largest amounts of nitrogen compounds. Such compounds are considered contaminants of the refining process, and interfere in the conversion steps to obtain lighter derivatives from the heavy fractions. In this study, the aim was to evaluate the removal of nitrogen compounds by adsorption process. Quinoline solution solubilized in toluene was used as a synthetic filler. Commercial activated carbons from coconut shell of babaçu and dendê in their original form and chemically modified with concentrated solutions of nitric and sulfuric acid, as well as sulfonated carbon developed from the rice husk, were evaluated for the adsorption capacity against compounds nitrogen residues present in the vacuum residue and synthetic charge. The textural characteristics of the adsorbents were also evaluated, in which it was observed that the modification with acid reduces the specific area of the activated carbons, but it promotes an increase in the removal of quinoline from the medium. From the preliminary batch adsorption test, the activated carbon from dendê treated with sulfuric acid (CDAS) was able to remove 67.08% of the quinoline present in the solution and was selected for kinetic and equilibrium study. The adsorption kinetics of quinoline were relatively fast for the three concentrations studied (500, 2000, 5000 mg L-1), reaching equilibrium after 240, 120 and 60 minutes of contact, respectively. The kinetic data for the three systems fit the pseudo-second order model better. The equilibrium data were better adjusted to the Freundlich model, revealing the physisorption character of adsorptive process. The maximum adsorption capacity obtained by Langmuir model was 56.63 mg g-1. The results show that CDAS is a promising adsorbent for the removal of quinoline in organic medium. In relation to the vacuum residue sample, batch adsorption tests were conducted in such a way to ascertain the efficiency in class N removal. The results of Mass Spectrometry, ESI (±) Orbitrap MS, showed that the adsorbents CBB and CBAN were more selective in the removal of the non-basic nitrogen compounds, while the basic nitrogenous ones were more persistent and were not removed by any of the adsorbents tested. / As frações pesadas do petróleo, especialmente o resíduo de vácuo, concentram as maiores quantidades de compostos nitrogenados. Tais compostos são considerados contaminantes do processo de refino, e interferem nas etapas de conversão para obtenção de derivados mais leves a partir das frações pesadas. Esta dissertação teve por objetivo avaliar a remoção de compostos nitrogenados por meio do processo de adsorção. Solução de quinolina solubilizada em tolueno foi utilizada como carga sintética. Carvões ativados comerciais de casca de coco de babaçu e de dendê, em suas formas original e modificados quimicamente com soluções concentradas de ácido nítrico e sulfúrico, além de carvão sulfonado desenvolvido a partir da casca de arroz, foram avaliados quanto à capacidade de adsorção frente a compostos nitrogenados presentes na carga sintética e no resíduo de vácuo (resíduo da última etapa de destilação do petróleo). As características texturais dos adsorventes também foram avaliadas, e foi observado que a modificação com ácido reduziu a área específica dos carvões, no entanto promoveu o aumento da remoção de quinolina do meio. A partir do teste preliminar de adsorção em batelada, o emprego do carvão ativado da casca de dendê tratado com ácido sulfúrico (CDAS) resultou na remoção de 67,08% da quinolina presente na solução e foi selecionado para estudo cinético e de equilíbrio. A cinética de adsorção da quinolina revelou um processo relativamente rápido para as três concentrações estudadas (500, 2000, 5000 mg L-1), atingindo o equilíbrio após 240, 120 e 60 minutos de contato, respectivamente. Os dados cinéticos, para os três sistemas, foram ajustados com sucesso ao modelo de pseudo-segunda ordem. Os dados de equilíbrio foram melhor ajustados ao modelo de Freundlich, revelando o caráter de fisissorção do processo adsortivo. A capacidade de adsorção máxima, obtida segundo modelo de Langmuir foi de 56,63 mg g-1. Os resultados mostram que o CDAS é um adsorvente promissor para a remoção de quinolina em meio orgânico. Em relação à amostra de resíduo de vácuo, ensaios de adsorção em batelada foram conduzidos de tal forma a averiguar a eficiência na remoção da classe N. Os resultados de Espectrometria de Massas, ESI (±) Orbitrap MS, mostraram que os adsorventes CBB e CBAN foram mais seletivos na remoção dos compostos nitrogenados não-básicos, enquanto os nitrogenados básicos mostraram-se mais persistentes, não sendo removidos por nenhum dos adsorventes testados.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The synthesis of a series of 3-haloacetyl-4-methyl-quinolines from the cyclocondensation reaction of 4-alkoxyvinyl ketones [R1C(O)CH=C(R2)(OCH3), where R1 = CF3, CCl3, CHCl2, CF2Cl, CF2CF3 and R2 = Me, Et, Pr, Bu, i-Bu, i- Pent] with 2-aminoacetophenone is reported. The reaction was performed in the presence of p-toluene sulphonic acid (p-TsOH), ionic liquid ([HMIM][TsO]) and under microwave irradiation. The molar ratio of the reactants 4-alkoxyvinyl ketone and 2-aminoacetophenone was of 1:1, respectively, for the quinoline with R1 = CHCl2, while for the other reactions was necessary a molar ratio of 1.2:1, respectively. The results showed that the combination of ionic liquid and microwave irradiation was effective for this synthesis, since the products were obtained with short rteaction times (10-20 min) and high yields (70-91%). In addition, the advantages of using the microwave irradiation method in comparison to the conventional thermal heating were also demonstrated. / Neste trabalho é descrita a síntese de uma série de 3-haloacetil-4-metilquinolinas a partir da reação de ciclocondensação de 4-alcoxivinil cetonas [R1C(O)CH=C(R2)(OCH3), onde R1 = CF3, CCl3, CHCl2, CF2Cl, CF2CF3 e R2 = Me, Et, Pr, Bu, i-Bu, i-Pent] com 2-aminoacetofenona. As condições reacionais utilizadas para a obtenção dos compostos heterocíclicos foram realizadas na presença d6 ácido p-tolueno sulfônico (ac. p-TsOH) e líquido iônico ([HMIM][TsO]) sob irradiação de micro-ondas. A relação molar empregada da 4-alcoxivinil cetona e da 2-aminoacetofenona foi de 1:1, respectivamente, para a quinolina R1 = CHCl2, enquanto que para as outras reações foi necessário uma relação molar de 1,2:1. Os resultados obtidos demonstraram que a combinação de líquido iônico e irradiação de micro-ondas foram eficazes para essa síntese, já que os produtos foram obtidos em tempo reacionais curtos (10- 20 min) e altos rendimentos (70-91%). Além disso, também foram mostradas as vantagens do método de irradiação de micro-ondas sobre o método convencional de aquecimento.

This study has focused on the synthesis of truncated analogues of the hydroxyethylene dipeptide isosteres, such as Ritonavir®, currently in clinical use as HIV-1 protease inhibitors. The reactions of pyridine-2- and quinoline-2-carbaldehydes with methyl acrylate, in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) or 3- hydroxyquinuclidine (3-HQ) as nucleophilic catalysts, have afforded a series of Baylis- Hillman adducts, acetylation and cyclisation of which have provided access to a series of indolizine-2-carboxylate esters. The carboxylic acids, obtained by base-catalyzed hydrolysis of these esters, have been coupled with various protected (and unprotected) amino compounds using the peptide coupling agent, 1,1’-carbonyldiimidazole (CDI), to afford a series of indolizine-2-carboxamides as indolizine-based truncated Ritonavir® analogues in quantitative yield. Aza-Michael reactions of pyridine-3-carbaldehydederived Baylis-Hillman adducts with various amino compounds have provided access to a range of pyridine-based products as mixtures of diastereomeric aza-Michael products. The assignment of the relative stereochemistry of the aza-Michael products has been established using 1-D and 2-NOESY experiments and computer modelling techniques. Computer modelling studies have also been conducted on selected aza-Michael products using ACCELRYS Cerius2 software, followed by interactive docking into the HIV-1 protease receptor site, using AUTODOCK 4.0. The docking studies have revealed hydrogen-bonding interactions between the enzyme and the synthetic ligands. Saturation Transfer Difference (STD) NMR experiments have also indicated binding of some of the aza-Michael products to the HIV-1 protease subtype C enzyme, thus indicating their binding and possible inhibitory potential.