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<p>A series of new methodologies to link a neurotransmitter receptor targeting vector (WAY) to carboranes and the preparation of the corresponding metallocarboranes (M = Re, ^99mTc) as a new class of organometallic CNS imaging probes is described. WAY-carboranes (<strong>5</strong>, <strong>6</strong>, <strong>16</strong>) and the corresponding metallocarboranes (M = Re (<strong>12</strong>, <strong>13</strong>, <strong>22a</strong>, <strong>22b</strong>), ^99mTc (<strong>14a</strong>, <strong>15</strong>, <strong>23</strong>)) were synthesized in yields ranging from 10-95%. The first observed 3,1,2 versus 2,1,8 rhenacarborane isomerization process was discovered for <strong>12</strong> where isomerization and complexation occurred simultaneously. Re-carboranes <strong>22a</strong> and <strong>22b</strong> had similar carbon-carbon cage configuration where electronic effects was the driving force behind isomerization.</p> <p>The lipophilicities of ^99mTc-carboranes (<strong>14a</strong>, <strong>15</strong>, <strong>23)</strong> were within the ideal range to cross the BBB (log P = 2.4-2.6). <em>In vitro</em> binding data showed that <strong>22b</strong> has high affinity for alpha-adrenergic receptors (K_i = 17-39 nM) resulting in the first organometallic complex to effectively bind to this class of receptors. SPECT images of <strong>14a</strong> in rats showed no brain uptake, while quantitative biodistribution studies indicated modest, non-negligible brain uptake in the hypothalamus region.</p> <p>The neutral [M(CO)₂(NO)(C₂B₉H₁₀R)] analogues (<strong>30</strong>, <strong>34</strong>, <strong>37</strong>) were prepared to address the limited brain uptake of the [M(CO)₃(C₂B₉H₁₀R)]^- complexes. Reactivity differences between Re and ^99mTc were noted during nitrosation conditions where the initial products from the reaction led to nitration of the phenyl group in addition to nitrosation of the metal core. The fluorescence properties of <strong>29</strong> were measured.</p> <p>Low yields and multistep syntheses associated with the preparation of substituted carborane led to the development of a carborane-alkyne platform. Alkyne-carboranes (<strong>53</strong>-<strong>55</strong>) were developed and conjugated to WAY-azide (<strong>46</strong>) using “click” chemistry. The metallocarboranes (M = Re (<strong>69</strong>-<strong>71</strong>), ^99mTc (<strong>72</strong>-<strong>74</strong>)) were generated in yields ranging from 45-71%.</p> / Doctor of Philosophy (PhD)

Antibiotic resistance has become and will continue to be a major medical issue of the 21st century. If not addressed, the potential for a post-antibiotic era could become a reality, one that the world has not been familiar with since the early 1900’s. Multidrug-resistant hospital-acquired bacterial infections already account for close to 2 million cases and 23,000 deaths in the United States, along with 20 billion dollars of additional medical spending each year. The CDC released a report in 2013 regarding the seriousness of antibiotic resistance and providing a snapshot of costs and mortality rates of the most serious antibiotic resistant bacteria, which includes 17 drug resistant bacteria, such as carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococcus and Staphylococcus aureus, and multidrug-resistant Acinetobacter and Pseudomonas aeruginosa. The development of antibiotic resistance is part of bacteria’s normal evolutionary process and thus impossible to completely stop. To ensure a future where resistant bacteria do not run rampant throughout society, there is a great need for new antibiotics and accordingly, methods to facilitate their discovery Macrolides are a class of antibiotics that target the bacterial ribosome. Since their discovery in the 1950’s medicinal chemistry has created semi-synthetic analogues of natural product macrolides to address poor pharmacokinetics and resistance. Modern X-Ray crystallography has allowed the chemist access to high resolution images of the bacterial ribosome bound to antibiotics including macrolides which has ushered in an era of structure-based design of novel antibiotics. These crystal structures suggest that the C-4 methyl group of third generation ketolide antibiotic telithromycin can sterically clash with a mutated rRNA residue causing loss of binding and providing a structural basis for resistance. The Andrade lab hypothesized that the replacement of this methyl group with hydrogen would alleviate the steric clash and allow the antibiotic to retain activity. To this end, the Andrade lab set out on a synthetic program to synthesize four desmethyl analogues of telithromycin by total synthesis that would directly test the steric clash hypothesis and also provide structure-activity relationships about these methyl groups which have not been assessed in the past. Following will contain highlights of the total synthesis of (-)-4,8,10-didesmethyl telithromycin, (-)-4,10-didesmethyl telithromycin, and (-)-4,8-desmethyl telithromycin and my journey toward the total synthesis of (-)-4-desmethyl telithromycin Traditional combinatorial chemistry uses chemical synthesis to make all possible molecules from various fragments. These molecules then need to be purified, characterized, and tested against the biological target of interest. While high-throughput assay technologies (i.e., automation) has streamlined this process to some extent, the process remains expensive when considering the costs of labor, reagents, and solvent to synthesize, purify, and characterize all library members. Unlike traditional combinatorial chemistry, in situ click chemistry directly employs the macromolecular target to template and synthesize its own inhibitor. In situ click chemistry makes use of the Huisgen cycloaddition of alkyne and azides to form 1,2,3-triazoles, which normally reacts slowly at room temperature in the absence of a catalyst. If azide and alkyne pairs can come together in a target binding pocket the activation energy of the reaction can be lowered and products detected by LC-MS. Compounds found in this way generally show tighter binding than the individual fragments. Described in the second part of this dissertation is the development of the first in situ click methodology targeting the bacterial ribosome. Using the triazole containing third generation ketolide solithromycin as a template we were able to successfully show that in situ click chemistry was able to predict the tightest binding compounds. / Chemistry

Carla Abarca Ph.D. Thesis / The selective separation of valuable minerals by froth flotation is a critical unit operation in mineral processing. Froth flotation is based on the ability of chemical reagents, called collectors, to selectively lower the surface energy of valuable mineral particles, facilitating attachment of the modified mineral particles to air bubbles in the flotation cell. The mineral laden bubbles rise to the surface forming a froth phase that can be isolated. Novel cationic polystyrene nanoparticle collectors have been developed recently to be used as effective flotation collectors, aiming to recover challenging nickel sulfide ores that respond poorly to conventional molecular flotation collectors. However, optimizing nanoparticle flotation collectors is a challenge. An effective nanoparticle collector candidate should meet three requirements: (1) it should be colloidally stable in the flotation media; (2) it should be hydrophobic enough to change the mineral surface and induce an air bubble-mineral particle attachment; and (3) specifically and strongly bind to metal-rich minerals. Producing nanoparticles that are simultaneously colloidally stable and sufficiently hydrophobic presents a problematic task. Thus, a delicate balance of nanoparticle properties is required for commercially viable nanoparticle collectors. This thesis presents a promising approach for discovering and characterizing novel nanoparticle collectors by using high throughput screening techniques. Developed was a workflow for fast fabrication and testing of nanoparticle candidates, including: (1) parallel production of large nanoparticle libraries covering a range of surface chemistries, (2) a high throughput colloidal stability assay to determine whether a nanoparticle type is stable in flotation conditions; (3) an automated contact angle assay to reject nanoparticles that are not hydrophobic enough to induce efficient bubble-particle attachment, and; (4) a laboratory flotation test in sodium carbonate (pH~10) with the best nanoparticle candidates. The automated colloidal stability assay was based on the optical characterization of diluted nanoparticle dispersions in multiwell plates, yielding critical coagulation concentrations (CCCs) of sodium carbonate. To pass this screening test, the CCC of candidate nanoparticles must be greater than the effective carbonate concentration in commercial flotation cells. Since the nanoparticle size affects the intrinsic light scattering properties of the nanoparticles, two routes were developed. The colloid stability assay was suitable for nanoparticles ranging between 50 nm and 500 nm, since nanoparticle size. The automated contact angle assay used a miniature 16-well plate format where flat glass slides were exposed to 200 μL nanoparticle dispersions. The cationic nanoparticles formed a saturated adsorbed monolayer on the glass, and after rinsing and drying, the water contact angle was automatically measured. Effective nanoparticle candidates had contact angles greater than 50 degrees, a criterion developed with model experiments. During the development of the automated workflow platform, a series of nanoparticles with methyl-ended PEG-methacrylate monomers were prepared. Although the PEG chains greatly enhanced colloidal stability, the particles were too hydrophilic to be effective collectors. Interestingly, nanoparticles with long PEG chains acted as froth modifiers, giving wetter and more robust foams as well as increased entrainment of materials that did not adhere to bubbles. Conventional laboratory scale latex synthesis methodologies are far too inefficient to generate large library of candidate nanoparticles. Instead, we started with a few parent nanoparticle types and then used Click chemistry to generate a large range of surface chemistries. Specifically copper-mediated azide alkyne cycloaddition reaction was used to functionalize the surface of azide nanoparticles with different chemical groups, ranging from hydrophilic amine-terminated PEG chains, to hydrophobic hexane-terminated materials. The Click library exhibited an extensive range of critical coagulation concentrations and contact angle values. For example, for a given parent azide nanoparticle, the contact angles ranged from 62 to 101 degrees, depending upon the density and type of click reagent. A novel paper chromatographic method was developed for the quantitative determination surface azide. This assay was critical for determining the surface density of functional groups from the click reactions. Overall, high throughput screening techniques were designed and applied to the development of nanoparticle collectors for froth flotation. Automated screening assays of critical coagulation concentration and contact angle proved to be effective in obtaining flotation domain maps, and finding the most promising nanoparticle collectors for froth flotation. I believe the work in this thesis is one of the first reported uses of high throughput methodologies for the development of mineral flotation reagents. / Thesis / Doctor of Philosophy (PhD) / Novel cationic polystyrene nanoparticle collectors have been developed to be used as effective flotation collectors, aiming to recover challenging nickel sulfide ores that respond poorly to conventional molecular flotation collectors. However, optimizing nanoparticle flotation collectors is a challenge. This thesis presents a promising approach for discovering and characterizing novel nanoparticle collectors by using high throughput screening techniques and click chemistry. Development of nanoparticle libraries and automated screening assays of critical coagulation concentration and contact angle proved to be effective in obtaining flotation domain maps, and finding the most promising nanoparticle collectors for froth flotation.

Cette thèse a pour objectif l’élaboration de nanoparticules hybrides à base de silice par microémulsion inverse. Les nanoparticules de silice constituent une matrice de base permettant de confiner et de protéger des molécules organiques et/ou des nanoparticules métalliques. L’incorporation combinée de différentes entités dans la silice ouvre ainsi de larges perspectives de par l'introduction de nouvelles propriétés liées à la structure hybride. Afin d’élaborer de tels objets, nous avons utilisé des micelles inverses à base d'eau, de Triton X-100, d'hexanol et de cyclohexane comme milieu réactionnel. L’influence des conditions opératoires sur le contrôle de la taille des micelles inverses a d'abord été étudiée. Ces micelles inverses ont ensuite été mises à profit comme nanoréacteurs pour la synthèse de nanoparticules de silice par procédé sol-gel en utilisant les précurseurs alkoxysilanes adéquats. Nous avons regardé dans quelle mesure il était possible de contrôler la taille des nanoparticules de silice en fonction du pourcentage d’eau par rapport au tensioactif. Il a ainsi été possible d’accéder de façon reproductible à des nanoparticules avec de tailles variables, de 30 nm à 200 nm. Nous avons ensuite regardé qu'il était possible d'encapsuler au sein de cette matrice nanométrique des fluorophores et des nanoparticules d’or et d’argent de façon contrôlée. En vue d’assurer une bonne stabilisation colloïdale en solution, ces nanoparticules hybrides ont été fonctionnalisées d'une part par ajout d'un silane fonctionnel et d'autre part par click chemistry. Nous avons ainsi pu montrer qu’il est possible d’effectuer dans un même milieu micellaire l’ensemble des processus de fabrication de la nanoparticule hybride, de la matrice de silice à sa fonctionnalisation en passant par l’incorporation d’entités fonctionnelles. Cette méthode de synthèse séquentielle nous a ainsi permis de supprimer les étapes de purification et de redispersion qui peuvent s’avérer problématiques dans les procédés classiques. L’ensemble de ce travail a été mis à profit pour la conception d’un agent antibactérien à base de nanoparticules argent/silice capables d’empêcher la prolifération bactérienne grâce au relargage progressif des ions argent. Les tests effectués en solution comme sur le coton et le polyéthylène téréphtalate imprégnés montrent effectivement un caractère antibactérien certain de ces systèmes. / This thesis aims at developing hybrid nanoparticles based on silica by reverse microemulsion. The silica nanoparticles are the basic matrix containing and protecting organic molecules and/or metallic nanoparticles. The combined incorporation of different entities within the silica opens wide prospects for the introduction of new properties related to the hybrid structure. To develop such objects, we used reverse micelles based on water, Triton X-100, hexanol and cyclohexan as reaction medium. The influence of operating conditions on the control of the size of reverse micelles was first studied. These micelles were then set to be used as nanoreactors for the synthesis of silica nanoparticles by sol-gel using suitable alkoxysilanes precursors. We monitored how it was possible to control the size of silica nanoparticles based on the water to surfactant ratio. It was thus possible to prepare in a reproducible way nanoparticles with sizes varying from 30 nm to 200 nm. We then investigated the possibility to encapsulate, in this nanoscaled matrix, fluorophores and nanoparticles of gold and silver in a controlled manner. To ensure a good colloidal stability in solution, these hybrid nanoparticles were, on the one hand, modified by adding a functional silane and, on the other hand, by click chemistry. We have thus shown that it is possible to perform, in a same micellar media, all of manufacturing process of the hybrid nanoparticle, from the silica matrix to its functionalization passing by the incorporation of functional entities. This method of sequential synthesis allowed us to bypass the purification and redispersion steps that can be problematic in the conventional methods. All this work has been extended to the design of an antibacterial agent based of silver/silica nanoparticles, capable of preventing bacterial growth through the gradual release of silver ions. Tests conducted in solution on the impregnated cotton and polyethylene terephtalate indeed show an interesting antibacterial character of these systems.

De acordo com a Organização Mundial de Saúde (World Health Organization - WHO), aproximadamente 40 milhões de pessoas ao redor do mundo estão infectadas com HIV/AIDS. Atualmente, a epidemia tem sido controlada em grande parte do mundo ocidental, porém, projeções sugerem que, até o fim desta década, o número de incidência da doença poderá duplicar. Apesar das significantes melhoras na morbidade e mortalidade de pacientes infectados pelo HIV, o rápido surgimento de cepas resistentes aos agentes anti-HIV, além dos efeitos adversos e o alto custo de fármacos de última geração, torna-se necessário o continuo desenvolvimento de novas classes de agentes anti-HIV. A transcrição e multiplicação do RNA viral são dependentes das interações seqüência-específica entre duas proteínas reguladoras virais essenciais, Tat e Rev, com seus respectivos sítios no RNA, TAR e RRE. Durante a última década, os aminoglicosídeos foram introduzidos como ligantes universais do RNA, sendo capazes de se ligar ao TAR e ao RRE. A literatura apresenta diversos aminoglicosídeos que são capazes de se ligar ao TAR e inibir a interação Tat-TAR bem como, inibir competitivamente a ligação da proteína Rev ao RRE, como, por exemplo, a neomicina e tobramicina. Considerando a importância dos aminoglicosídeos e análogos nucleosídicos, conhecidamente eficazes na terapia antirretroviral, o trabalho foi direcionado para a síntese de conjugados de aminociclitol, 2- desoxi-estreptramina, e adenosina, bem como, dímeros de adenosina via estratégia de click chemistry por reação de cicloadição azido-alcino catalisada por Cu(I) (CuAAC). Para a síntese destes produtos, o precursor adenosina foi convertido no derivado 5\'-azido-5\'- desoxi-adenosina, o qual foi condensado com diversos diinos terminais comerciais, contendo diferentes grupos espaçantes, com a finalidade de explorar suas influências nas propriedades eletrônicas e estéricas nos conjugados de interesse frente à atividade anti-HIV. Os derivados alcinos presentes na posição C-5\' de adenosina, via grupo triazol, foram empregados para a síntese dos monômeros nucleosídeo-aminociclitóis, assim como, na síntese de dímeros nucleosíde0-aminociclitóis, via reação de cicloadição 1,3-dipolar, na presença de CuSO4, quantidade catalítica, e ascorbato de sódio, para geração in situ de Cu(I). Adicionalmente, alguns dos compostos, na concentração de 1mM, foram testados empregando o ensaio de ELISA para detecção da presença de proteína viral p24 em linhagem células H9 e avaliação de sua atividade antirretroviral. De acordo com o ensaio biológico, um dos compostos preparados apresentou, proporcionalmente ao crescimento da linhagem H9 (HIV) controle, atividade de inibição de formação da proteína viral p24 similar ao composto padrão zidovudina (AZT). Além disso, outros dois compostos também apresentaram um resultado relevante uma vez que suas atividades foram similares ao composto padrão lamivudina (3TC). Estes resultados sugerem que a presença de uma cadeia metilênica mais extensa, como cadeia lateral ou grupo espaçante, pode influenciar positivamente a atividade biológica por efeito hidrofóbico ou estérico. Por fim, os ensaios de viabilidade celular demonstraram que os compostos testados não foram citotóxicos nas condições testadas. / According to World Health Organization - WHO about 40 million of people are infected with HIV/AIDS. Currently, the epidemic has been controlled largely in the western world, since, projections suggest that, until this decade end, the disease incidence could increase. Despite significant improvements in morbidity and mortality of HIV-patients, quick emergence of resistant strains to anti-HIV agents, in addition to adverse effects and high cost of recent drugs, becomes necessary the ongoing development of new classes of HIV agents. Transcription and translation of the viral RNA are dependent of sequence-specific interactions among two essential viral regulatory proteins, Tat and Rev, and their corresponding TAR and RRE sites in HIV-1 RNA. Over the past decade, aminoglycosides were established as universal RNA linkers, being able to link to TAR and RRE. The literature reports several aminoglycosides that bind to TAR and inhibit Tat-TAR interaction, as well as, competitively inhibit the bind between Rev protein and RRE, such as: neomycin and tobramycin. Considering the importance of nucleosides analogs, effective in antiretroviral therapy, and aminoglycosides, the work was driven to the synthesis of aminocyclitol, 2- deoxy-streptamine, conjugated to the adenosine, as well as, conjugated dimers of adenosine by molecular duplication via click chemistry strategy involving copper-catalysed azide-alkyne cycloaddition reaction (CuAAC). For the synthesis of these products, the starting material adenosine was converted to 5\'-azide-5\'-deoxy-adenosine, which was conjugated with several commercials terminal dialkynes containing different intercalating groups in order to explore the influences of the steric and electronic properties of conjugates towards anti-HIV activity. Alkynes derivated at C-5\' position of adenosine, via triazole group, were used in the synthesis of nucleoside-linked aminocyclitols, as well as, nucleoside conjugated dimers by 1,3-dipolar cycloaddition reaction under microwave-assisted conditions (MW), using the catalytic system CuSO4/sodium ascorbate for the in situ generation of Cu(I). Additionally, several compounds, at concentration of 1mM, were tested in vitro by ELISA for detection of p24 protein in H9 cells to antiretroviral evaluation. According with the biologic assay, one of the compounds showed inhibition of p24 protein production similar to zidovudine (AZT), when compared to H9 cells line growth control, Furthermore, two compounds also showed important activities similar to lamivudine (3TC). These results suggest that the presence of a longer methylenic chain, as side chain or intercalating groups, could influence positively in the biologic activity due to hydrophobic or steric effects. Ultimately, the cell viability assays showed that compounds were not cytotoxic in the tested conditions.

La contamination des surfaces par des bactéries et l’émergence de souches résistantes aux antimicrobiens sont des problèmes très préoccupants dans différents domaines tel que les domaines hospitalier et alimentaire. Cette contamination commence par l’adhésion de bactéries pathogènes sur une surface jusqu’à la formation de biofilms. Ces derniers contribuent à l’émergence de résistances de certaines souches bactériennes aux traitements conventionnels. Pour répondre à ces problèmes de contamination des surfaces, ces travaux de thèse portent sur le développement de nouveaux matériaux antibactériens à base de fibres de pâte à papier. Nous nous sommes intéressés, dans une première partie, à l’élaboration d’un papier antibactérien par le greffage, via un lien triazine, de deux composés d’huiles essentielles, le thymol et le carvacrol, connus pour leurs activités antibactériennes. L’évaluation microbiologique des matériaux élaborés, sur les deux souches bactériennes testées, E.coli et S.aureus, a montré un effet bactériostatique. Ces matériaux bloquent donc la croissance bactérienne empêchant ainsi la formation des biofilms. Une synergie entre le thymol et le carvacrol lorsqu’ils sont greffés sur les fibres de pâte à papier a également été montré. Dans une deuxième partie, notre étude s’est focalisée sur l’élaboration d’un papier antibactérien qui n’acquière son activité qu’après greffage et formation du motif actif « aryl-1,2,3-triazole ». Le greffage est réalisé par une réaction de « Click Chemistry », la cycloaddition de Huisguen catalysée par le cuivre I. Les tests antibactériens révèlent l’importance du substituant de l’aryle, l’influence du temps de contact et la pertinence d’utiliser des mélanges de matériaux. L’activité antibactérienne observée sur les fibres de la pâte thermomécanique est meilleure dans les deux parties. Les différents résultats obtenus sont décrits dans ce manuscrit. / The contamination of surfaces by bacteria and the emergence of antimicrobial resistant strains are very worrying problems in different areas such as hospital and food. This contamination begins with the adhesion of pathogenic bacteria on a surface until the formation of biofilms. These biofilms contribute to the emergence of resistances of certain bacterial strains to conventional treatments. To answer these problems of surface contamination, this thesis work focuses on the development of new antibacterial materials based on pulp fibers. In the first part, we focused on the development of an antibacterial paper by grafting, via triazine link, two essential oil compounds, thymol and carvacrol, known for their antibacterial activities. The microbiological evaluation of the developed materials against the two bacterial strains tested, E. coli and S. aureus, showed a bacteriostatic effect. These materials block the bacterial growth thus preventing the biofilms formation. Synergy between thymol and carvacrol grafted onto paper has also been shown. In a second part, our study focused on the development of an antibacterial paper that acquires its activity only after the grafting and formation of "aryl-1,2,3-triazole", the active motif. The grafting is carried out by a reaction of "Click Chemistry", the copper (I)-catalyzed Azide Alkyne Cycloaddition. The antibacterial tests reveal the importance of the aryl substituent, the influence of the contact time and the relevance of using mixtures of materials. The antibacterial activity observed on the thermomechanical pulp fibers is better in both parts. The different results obtained are described in this manuscript.

A la suite des nombreux travaux sur l’inhibition de la glycogène phosphorylase (GP) menés au laboratoire et au travers de diverses collaborations, cette thèse décrit en cinq chapitres suivis d’une partie expérimentale détaillée, les dernières avancées en termes de synthèse et d’évaluation biologique des inhibiteurs du site catalytique de la GP. La chapitre I de ce manuscrit est consacrée à la présentation des diabètes et plus particulièrement du diabète de type II dont le traitement, motivation première de ce projet, repose sur la connaissance des mécanismes complexes régulant la glycémie. Les différents inhibiteurs synthétisés sont classés par famille selon leur structure qui associe un aglycone hétérocyclique, susceptible d’affinité pour le canal β proche du site actif de l’enzyme, avec un motif glycopyranosidique, ou glycopyranosylidène dans le cas des motifs spiro. Le chapitre II est consacré aux inhibiteurs spiro-bicycliques tels que les glucopyranosylidène-spiro-1,4,2-oxathiazoles et les glucopyranosylidène-spiro-isoxazolines. Le chapitre III décrit la synthèse de C- et N-glycosyles hétérocycles, principalement des glycopyranosyl-1,2,3-triazoles. Enfin le chapitre IV décrit la fonctionnalisation de 5-halogéno-1,2,3-triazoles 4-substitués par couplages pallado-catalysés qui ont constitué un développement imprévu mais original des travaux. Pour terminer, le chapitre V décrit l’évaluation des molécules préparées en tant qu’inhibiteurs de la glycogène phosphorylase. Les expériences et résultats d’enzymologie, de cristallographie ainsi que les tests cellulaires in vitro et in vivo sur le rat sont présentés / Following many studies lead on the inhibition of glycogen phosphorylase (GP) in our laboratory an trough several collaborations, this thesis describes in five chapters and a detailed experimental section, the most recent advances in the areas of synthesis and biological evaluation of GP’s catalytic site inhibitors. Chapter I is dedicated to the description of diabetes and especially type 2 diabetes of which treatment, the main goal of this project, requires knowledge of the complex mechanisms that regulates glycemia. Synthesized inhibitors are broken down into families according to their structure which associates an heterocyclic aglycon, prone to binding in the β pocket lining the active site, with a glycopyranoside or glycopyranosylidene moiety in the case of spiro compounds. Chapter II focuses on spiro-bicyclic inhibitors such as glucopyranosilidene-spiro-1,4,2-oxathiazoles and glucopranosylidene-spiro-isoxazolines. Chapter III describes the synthesis of C- and N-glycosyl-heterocycles, mainly glycopyranosyl-1,2,3-triazoles. Finally, chapter IV studies the palladium-mediated cross coupling fonctionalization of 4-substituted-5-halogenated-1,2,3-triazoles that represents an unexpected but interesting development of the project. To conclude, chapter V gathers the evaluation of synthesized molecules as GP inhibitors. Enzymology and crystallography as well as in vitro and in vivo experiments are presented