Protein translocation is essential for bacterial survival and the most important translocation mechanism in bacteria is the secretion (Sec) pathway. Thus targeting Sec pathway is a promising strategy for developing novel antibacterial therapeutics. We report the design, syntheses, mechanistic studies and structure-activity relationship studies using HQSAR and 3-D QSAR Topomer CoMFA analyses of 4-oxo-5-cyano thiouracil derivatives. In summary, introduction of polar group such as –N3 and linker groups such as –CH2-O- enhanced the potency as well as logP and logS several fold. We also report the discovery, optimization and structure-activity relationship study of 1,2,4-triazole containing pyrimidines as novel, highly potent antimicrobial agents. A number of inhibitors have been found to inhibit microbial growth at high nanomolar concentrations.

Na primeira parte deste trabalho apresentamos uma forma eficiente para sintetizar quinze novos compostos α-amino-1,3-dicarbonílicos através da reação multicomponente de Ugi. Para estas sínteses foi utilizado o microrreator de fluxo contínuo, um aparelho que possibilita uma excelente transferência de calor, de massa e alta relação superfície / volume. Algumas das vantagens em se utilizar um microrreator de fluxo contínuo na síntese são: redução do tempo de reação, aumento de rendimento, seletividade das reações e menor geração de resíduos. Foi possível assim estudar as reações químicas em condições inéditas, variando parâmetros como: temperatura, pressão, tempo de residência e relação estequiométrica. Um comparativo de rendimento da síntese de quatro moléculas foi realizado e pôde-se notar a eficiência do equipamento utilizado, pois os rendimentos obtidos foram superiores quando as mesmas moléculas foram sintetizadas através da reação one-pot. Um scale-up da reação de Ugi também foi realizado e apresentou um resultado satisfatório. Na segunda parte alguns destes compostos foram utilizados como intermediários na formação de uma ligação amídica e também aplicamos a metodologia relacionada à cicloadição catalisada por cobre entre alquinos e azidas na síntese de cinco novos compostos 1,2,3-triazóis. Este foi o primeiro trabalho realizado no Laboratório de Compostos Heterocíclicos da Faculdade de Ciências Farmacêuticas utilizando o microrreator de fluxo contínuo e este equipamento atendeu as necessidades deste trabalho com efetividade. / The first part of this work we present an efficient way to synthesize fifteen new α-amino-1,3-dicarbonyl compounds through the multicomponent Ugi reaction. For these syntheses was used the continuous flow micro-reactor, an equipment that allows an excellent transfer of heat, mass and high surface / volume ratio. Some of the advantages of using a continuous flow micro-reactor in the synthesis are: reduction of reaction time, increase of yield, selectivity of reactions and less generation of residues. It was possible to study the chemical reactions under new conditions, varying parameters such as: temperature, pressure, residence time and stoichiometric ratio. A yield comparison of the synthesis of four molecules was carried out and it was possible to note the efficiency of the equipment used, because the obtained yields were superior when the same molecules were synthesized through the one-pot reaction. A scale-up of the Ugi reaction was also performed and presented a satisfactory result. In the second part some of these compounds were used as intermediates in the formation of an amide bond and we also apply the methodology related to the copper catalyzed cycloaddition between alkynes and azides in the synthesis of five new 1,2,3-triazoles compounds. It was the first work performed in the Laboratory of Heterocyclic Compounds of the Faculty of Pharmaceutical Sciences using the continuous flow micro-reactor and this equipment met the needs of this work with effectiveness.

As cumarinas são compostos com potente atividade biológica. Foi explorada sua funcionalização, iniciando pela sua bromação, gerando o composto 3-bromocumarina, utilizado como material de partida para as reações de acoplamento do tipo Suzuki-Miyaura, que são uma das reações mais empregadas para a formação de ligação carbono-carbono, a qual utiliza paládio como catalisador e ácidos e ésteres borônicos como nucleófilo. Esses ácidos e ésteres borônicos possuem desvantagens, por isso foram substituídos pelos sais de organotrifluoroboratos de potássio, que são mais nucleofílicos, estáveis à umidade e à luz e não são higroscópicos. Assim, foi associada a catacterística reativa da cumarina para gerar derivados cumarínicos. Foram utilizados sais de ariltrifluoroboratos de potássio na primeira etapa e alquiniltrifluoroboratos de potássio na segunda etapa. Após o término destas duas etapas, foi utilizado o acoplamento de Sonogashira para a geração de um segundo material de partida, o 3-etiniltrimetilsililcumarínico, para poder sintetizar os 1,2,3-triazolilcumarínicos através da 1,3-dipolar cicloadição de Huisgen. Os 1,2,3-triazóis também possuem vasta atividade biológica, sendo de grande interesse sua preparação. / The coumarins are compounds with great biologic activity, for this reason in this dissertation we explored the functionalization beginning with bromination, generating the compound 3-bromocoumarin, used as starting material for the Suzuki-Miyaura cross-coupling reactions.The Suzuki-Miyaura cross-coupling reactions is one of the most employed protocol for carbon-carbon bond formation that use palladium as catalyst, boronic acid and ester as nucleophiles. But this boronic acid and ester have drawback and were substituted for potassium organotrifluoroborate salts that are more nucleophilic, moisture and light stable and are not hygroscopic. In this context, we associated the coumarin reactivity characteristic with the methodology mentioned above for create coumarin derivatives. We used potassium aryltrifluoroborate salts in the first step and potassium alkynyltrifluoroborate salts for the second step. After finished both steps mentioned before, we used the Sonogashira coupling to create the second starting material, the 3-((trimethylsilyl)ethynyl)-2H-chromen-2-one, so we could synthesize the 1,2,3-triazolyl coumarins through Huisgen 1,3-dipolar cycloaddtion. The 1,2,3-triazole also have a huge biologic activity, that represent a large interest for your preparation.

The majority of this dissertation focuses on proton conducting materials that could be used at high operating temperatures. Higher operating temperatures are desirable as they will increase fuel cell efficiency, reduce cost, and simplify the heat management system. The factors governing proton conduction including segmental mobility, protogenic group identity, and charge carrier density were investigated on a variety of polymers containing 1H-1,2,3-triazole moieties. Proton conductivity measurements were made using AC impedance spectroscopy. Random copolymers and terpolymers of triazole-containing acrylates and poly(ethylene glycol)methyl ether acrylate (PEGMEA) have been synthesized. Conductivity increased with increasing degree of PEG incorporation until reaching a maximum at 30% mole PEGMEA. In comparison to benzimidazole-functionalized polyacrylate with 35% mole PEGMEA, the triazole analog showed a higher proton conductivity, and a less pronounced conductivity temperature dependence. Further increases in conductivity was achieved through the addition of trifluoroacetic acid. To study the effect of charge carrier density on proton conduction, polyacrylates containing a different number of triazole groups per repeat unit were synthesized. The result showed that introduction of more than one triazole per repeat unit did not result in an increase in conductivity as there was an accompanying increase in Tg. To improve the thermal and mechanical properties, triazole groups were tethered to a higher Tg backbone polymer, polynorbornene. Introduction of polyhedral oligomeric silsesquioxane (POSS) into triazole-functionalized polynorbornene was also investigated. In a parallel set of investigations, poly(2-(dimethylamino)ethyl methacrylate), PDMAEMA, and copolymers of DMAEMA and methyl methacrylate (PDMAEMA-co-PMMA) were synthesized via atom transfer radical polymerization (ATRP). Fluorescently-labeled PDMAEMAs were synthesized using fluorescent ATRP initiators to ensure the presence of one dye molecule on every polymer chain. PDMAEMAs and PDMAEMA-co-PMMA with different molecular weights have been deposited onto a negatively-charged silica surface via controlled flow deposition. The results show that the polymer deposition rate depends on molecular weight, and is inversely proportional to molecular weight. A preliminary adhesion study of 1-μm negatively charged silica spheres onto these functionalized surfaces indicates that by varying the molecular weight, the adhesion threshold can be changed. System modeling is being conducted to support experimental observations.

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Aspergillus fumigatus is a globally present opportunistic fungal pathogen that plays a key role in degrading organic matter. A. fumigatus can cause a vast array of diseases, collectively known as aspergilloses. The most serious of these is invasive aspergillosis, that has a mortality rate of 30 to 95% with treatment. Recent studies have indicated that the global A. fumigatus population consists of multiple divergent genetic clusters that are broadly distributed geographically. However, most of the previously analyzed samples have come from continental Eurasia and the Americas where the effects of historical or contemporary gene flow is difficult to distinguish. My thesis project, therefore, focused on analyzing the genetic diversity of the Auckland, New Zealand A. fumigatus population, as it is geographic distant from all previously analyzed populations. Here, we obtained 104 A. fumigatus isolates from Auckland and compared the genotypes of these isolates to population data obtained from nine other countries from Europe, Africa, North America, and Asia. The goal was to analyze the potential effects of historical differentiation and gene flow within this population. We determined that the Auckland population had a low, non-significant level of differentiation compared to most previously surveyed global populations. However, the Auckland population also contained unique genetic elements not present within populations from other geographic regions. Though the hypothesis of random recombination was rejected, we found abundant evidence for phylogenetic incompatibility and recombination within the Auckland A. fumigatus population. Lastly, we identified two triazole resistant strains within the Auckland population, with one carrying the common TR34/L98H cyp51A mutation. Our results suggest that contemporary gene flow, likely due to anthropogenic factors, is a major force shaping the New Zealand A. fumigatus population. These results contribute to our understanding of the high levels of gene flow observed within and among many geographic populations of A. fumigatus. / Thesis / Master of Science (MSc) / Aspergillus fumigatus is a globally distributed fungal mold capable of causing serious diseases in individuals with weakened immune systems or lung damage. In the environment, A. fumigatus lives in the soil where it degrades organic matter and contributes to the cycling of nitrogen and carbon across the planet. Due to the airborne nature of its spores, people inhale this fungus daily, and those at risk may develop disease. These diseases, collectively known as aspergilloses, can result in long term chronic illnesses, and in the case of invasive aspergillosis, the death rate can be as high as 95%, even with treatment. Medical treatment of aspergilloses involves the use of antifungal drugs. However, some A. fumigatus strains have developed resistance. I am interested in the patterns of global genetic diversity of A. fumigatus populations. For my MSc thesis, I investigated the A. fumigatus population within Auckland, New Zealand, as it is both geographically isolated and distant from other previously surveyed populations. Our data illustrated that the New Zealand population contains pockets of unique diversity as well as high levels of similarity to the previously surveyed populations within Europe. My results suggest that human influences, likely due to travel and trade, have played a large role in shaping the genetic diversity of the A. fumigatus population from Auckland, New Zealand.

La chimie de clic est devenue indispensable dans les nombreux domaines de chimie associée à la conception de médicament. Dans ce contexte, comme nous savons(connaissons) l'étude concernant l'impact d'insertion triazole sur la conformation de peptaibol est limitée, nous avons conduit l'étude pour examiner l'impact et l'adaptabilité de 1, 1 4-disubstituted, 2, l'insertion 3-triazole dans peptaibols différent. Selon le résultat de cette expérience touchant à l'activité réduite et la conformation perturbée de l'analogue peptaibol, le substitut dipeptide décoré du fragment triazole portant substituents hydrophobe divers a été inséré à très N-ter la partie du peptaibol. L'amélioration du bioactivity et de la restauration de la conformation pour les analogues peptaibol a été observée et le fait a été aussi soutenu par les résultats obtenus de l'étude biophysique des analogues choisis d'ALM F50/5. Nous avons plus loin prolongé notre étude pour employer notre stratégie à être appliqué sur le peptide P42 thérapeutique qui souffre de la limitation de manque de perméabilité et de stabilité. Le peptide P42 est impliqué dans le pathophysiology de la maladie d'Huntington neurodégénératif. Un total de 12 analogues de peptide de P42-camelote a été synthétisé par SPPS par notre protocole optimize. Dans la deuxième partie, nous avons développé une stratégie pour synthétiser lipopeptide cyclique produit de l'espèce cynaobacterial marine. Notre objectif principal était de synthétiser Hormothamnin A, undecapeptide cyclique consistant de plusieurs acides aminés artificiels incluant dehydroamino acide (Dhaa) qui fait la synthèse de ce peptide compliqué. En raison de cette raison, premièrement, nous avons voulu appliquer notre stratégie de synthétiser Trichormamide A, une sorte relativement plus simple de cylic lipopeptide. Après l'accomplissement de cette tâche, une première tentative a été faite pour synthétiser Hormothamnin A. Le résultat préliminaire de ceci est présenté dans cette section. Enfin, nous avons essayé de développer une méthodologie robuste pour synthétiser Fmoc-Dhaa dans la phase de solution et son insertion dans l'ordre peptaibol par une norme(un standard) SPPS le protocole. Les résultats préliminaires que nous avons concernant la synthèse Dhaa et son insertion dans peptaibol sont aussi discutés ici de plus avec la synthèse de phase solide de Bergofungin naturel D. / The click chemistry has become indispensible in the many areas of chemistry associated with drug design. In this context, as we know the study concerning the impact of triazole insertion on the conformation of peptaibol is limited, we have conducted the study to investigate the impact and adaptability of the 1, 4-disubstituted 1, 2, 3-triazole insertion into different peptaibols. Depending on the outcome of this experiment relating to reduced activity and perturbed conformation of the peptaibol analogue, the dipeptide surrogate decorated with the triazole moiety bearing various hydrophobic substituents was inserted at the very N-ter part of the peptaibol. The improvement of the bioactivity and restoration of the conformation for the peptaibol analogues was observed and the fact was also supported by the results obtained from the biophysical study of the selected analogues of ALM F50/5. We have further extended our study to employ our strategy to be applied on the therapeutic P42 peptide which suffers from the limitation of lack of permeability and stability. P42 peptide is involved in the pathophysiology of neurodegenerative Huntington’s disease. A total of 12 analogues of P42-TAT peptide were synthesized through SPPS by our optimized protocol. In the second part, we have developed a strategy for synthesizing the cyclic lipopeptide originated from marine cynaobacterial species. Our main objective was to synthesize Hormothamnin A, a cyclic undecapeptide consisting of several unnatural amino acids including dehydroamino acid (Dhaa) which makes the synthesis of this peptide complicated. Due to this reason, firstly, we have chosen to apply our strategy to synthesize Trichormamide A, a relatively simpler kind of cylic lipopeptide. After accomplishing this task, a first attempt was made to synthesize Hormothamnin A. The preliminary result of this is presented in this section. At last, we have tried to develop a robust methodology to synthesize Fmoc-Dhaa in solution phase and its insertion into the peptaibol sequence through a standard SPPS protocol. The preliminary results we have got concerning the Dhaa synthesis and its insertion into peptaibol are also discussed here in addition with the solid phase synthesis of natural Bergofungin D

Ce travail s’inscrit dans le domaine des cages moléculaires, édifices dont la géométrie définit unecavité tridimensionnelle capable de contenir d’autres entités.L’objectif de cette thèse est la synthèse de cages moléculaires covalentes possédant despropriétés d’encapsulation et une taille modulables. Les cages synthétisées avec succèsincorporent des porphyrines de zinc ou bases libres, ainsi que huit ligands triazoles périphériques.Des molécules ont pu être encapsulées par coordination aux porphyrines ou par interactions π, cequi démontre la capacité de la cage à s’adapter à l’invité grâce à sa flexibilité. La coordinationd’ions argent(I) permet de passer d’une conformation aplatie à une conformation ouverte. Lecaractère commutable de la cage a été démontré par décoordination de ces ions. Enfin, lacoordination d’ions argent(I) aux ligands de la cage augmente la stabilité de deux ligandsditopiques, le DABCO et la pipérazine, au sein de la cavité. Elle permet aussi l’accès de la cavité àdes molécules non encapsulées en l’absence d’argent(I). Ces résultats démontrent le contrôleallostérique de l’encapsulation de molécules par un stimulus chimique. / This work belongs to the field of molecular cages, hollow structures enclosing a three-dimensionalcavity able to encapsulate other molecules.The goal of this thesis include the synthesis of molecular covalent cages with a controllablecavity size able to perform switchable guest encapsulation. A DABCO-templated click reactionafforded three flexible covalent cages, endowed with two zinc(II) or free-base porphyrins and eightperipheral triazole ligands. Various guest molecules could be encapsulated by coordination toporphyrins or π-π interactions, in an induced-fit mechanism, probing the ability of the cage to adaptto the guest thanks to its flexibility. Coordination of silver(I) ions to the peripheral triazoles allow toswitch from a flattened to an open and locked conformation. Removal of the ions proved thecommutability of the cage. Finally, coordination of silver(I) ions to triazole ligands increase thestability of two ditopic ligands, DABCO and piperazine, inside the cavity. It also allowed the accessto the cavity of molecules that were not otherwise encapsulated. These results shows the allostericcontrol of guest encapsulation by a chemical stimulus.