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Dissertations / Theses on the topic 'Azole'
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1
Miró, Sabaté Carlos Hector. "Azole-based energetic materials." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-99477.
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Howard, Susan J. "Azole Resistance in Aspergillus." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503743.
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Sabzevari, Omid. "Azole antifungal drugs and cytochrome P450 induction." Thesis, University of Surrey, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359878.
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Albarrag, Ahmed. "Azole resistance in clinical isolates of Aspergillus fumigatus." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487927.
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Aspergillus fil1nigatus is the most common aetiological agent of aspergillosis. Invasive aspergillosis is a major cause of death in leukaemic and organ transplant patients. The azoles are the largest and the most widely used class of antifungals. Antifungal drug resistance has been observed in many fungi. In many organisms, acquiring resistance to a drug can confer a biological fitness cost that is expressed for example as decreased growth rate or virulence. A total number of 21 A. fill11igatus clinical isolates were used in this project. Sixteen of these isolates were recovered serially from four patients at different times during the treatment period with azoles, including three cases of acquired azole resistance. The antifungal susceptibilities of isolates were determined. The genetic relatedness of the isolates was confirmed by microsatellite length polymorphism typing. Various measures of fitness were used to determine variation between susceptible and resistant isolates. Growth rate (colony radial growth rate and specific growth rate), germination time and conidial yields were determined on various media. Although some resistant isolates had a reduced growth rate compared to their susceptible match, there was no clear evidence of fitness cost of resistance has been found. The mechanisms of drug resistance in these isolates were investigated. Sequencing of the cyp5JA gene was carried out. Novel and previously described mutations in cyp5JA were identified. Three new mutations were detected in isolates recovered from patient D which were shown to have the same genotype. These mutations were G138C (in six isolates), Y431C (in one isolate) and G434C (in one isolate). These isolates have decreased susceptibility to itraconazole (>8.0 mg/l), voriconazole (4-8.0 mg/l), ravuconazole (4-8.0 mg/l), and posaconazole 0-4.0 mg/l). Azole cross-resistance observed in these isolates was confirmed to be caused by two of these mutations, G138C and Y431C, by expression of the mutated cyp5JA alleles in the yeast S. cerevisiae. The relative levels of expression of cyp5JA, cyp5JB and five efflux transporters, AfuMDRJ, AfilMDR2, AfiIMDR3, AfuMDR4 and atrF, genes were analysed using real-time RT-PCR. Gene expression analysis revealed that isolates from patient D had their cyp5JA gene up-regulated by 7.2- to 13.4-fold. Generally, susceptible and resistant isolates had the same level of expression of all five efflux transporters examined. Interestingly, a type II transposon insertion (1882 bp) in the region upstream of the start codon of cyp5JA, at position -317, was detected in one isolate from patient D, which exhibited the highest level of cyp5JA expression and so transposon insertion was associated with elevation of cyp5JA expression. In conclusion, this thesis describes novel mutations in the cyp5JA gene of clinical isolates that confer and azole cross-resistance. It also identified up-regulation of the cyp5JA gene as an additional azole resistance mechanism in some isolates. An active transposon was identified and found to be associated with resistance by elevating gene expression, an observation not previously made in A. fill11igatus for any phenotype. Up-regulation of 5 transporters and mutations in the cyp5JB gene were not related to resistance.
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Venkateswarlu, Kanamarlapudi. "Azole antifungal drugs mode of action and resistance." Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389558.
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Marichal, Patrick. "Molecular mechanisms of azole resistance in human pathogenic fungi." Maastricht : Maastricht : Universiteit Maastricht ; University Library, Maastricht University [Host], 1999. http://arno.unimaas.nl/show.cgi?fid=6858.
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Liu, Teresa T. "Transcriptional regulation of azole antifungal resistance in candida albicans." View the abstract Download the full-text PDF version, 2008. http://etd.utmem.edu/ABSTRACTS/2008-023-Liu-index.html.
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Thesis (M.S.)--University of Tennessee Health Science Center, 2008.Title from title page screen (viewed on July 31, 2008). Research advisor: P. David Rogers, Pharm.D., Ph.D. Document formatted into pages (xii, 172 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 98-115).
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Lamb, David Christopher. "Cytochrome P450 inhibition and azole antifungal mode of action." Thesis, University of Sheffield, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296853.
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Davies, James Robert. "Novel and target specific synthesis of 1,3-azole systems." Thesis, University of Exeter, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408735.
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Kwok, Iris Man Yan. "The biochemical mode of action of newer azole fungicides." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336186.
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Nakamuro, Takayuki. "New Reactions Using Diazo Intermediates Generated from Azole Compounds." Kyoto University, 2018. http://hdl.handle.net/2433/232059.
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Rodrigues, de Melo Nadja. "Fungal azole resistance and the role of cytochrome P450." Thesis, Swansea University, 2007. https://cronfa.swan.ac.uk/Record/cronfa42593.
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The incidence of fungal infections and particularly infections caused by non- albicans Candida species has increased considerably in the past two decades. The azole antifungal drugs are central to the management of fungal infections and like the use of other antibiotics drug resistance has emerged. Factors associated with antifungal resistance were investigated including azole susceptibility, drug accumulation and membrane sterol composition. Intracellular drug accumulation in Candida strains and species was examined and a clear correlation to microbial sensitivity was not observed. Also the membrane sterol profiles of some resistant strains were also altered with an increase in intermediates sterols, but no clear evidence of new mutants of sterol biosynthetic enzymes was uncovered. Some clinical strains were found to be resistant to specific azoles where other strains were resistant to a broad spectrum of azoles. The fungal cell wall and its biosynthesis are essential for cell viability and as such are potential targets for novel antifungal agents. CYP56 in S. cerevisiae encodes a cytochrome P450 enzyme that catalyses the biosynthesis of dityrosine during spore wall biogenesis. The role of the C. albicans CYP56 gene in growth and drug susceptibility was investigated. The full-length CYP56 DNA sequence was determined and the gene disrupted using the SAT 1-flipper technique. The mutant exhibited increased susceptibility to caspofungin and nikkomycin compared to the wild-type parental strain, whereas susceptibility to azoles and other metabolic inhibitors tested was unaffected. Phenotypically, the wild-type and mutant strains were morphologically similar on rich media, however in minimal media the cyp56tDelta mutant exhibits hyphal growth in contrast to the yeast only form of the parental wild-type strain. Also the mutant failed to form chlamydospores. Over- expression of CYP56 protein in E. coli produced a membrane-associated cytochrome P450 enzyme that catalysed the conversion of N-formyl tyrosine to N-formyl dityrosine when reconstituted with a fungal cytochrome P450 reductase in liposomes. The present study aimed to further the understanding of the biological, genetic and physiological aspects azole effect on clinical strains, on fungal CYPs (including CYP56) and for sterol biology associated with fungi, particularly in Candida species.
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Pérez, Cantero Alba. "Study and characterization of azole resistance in Aspergillus section Nigri." Doctoral thesis, Universitat Rovira i Virgili, 2020. http://hdl.handle.net/10803/670198.
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Algunes espècies d'Aspergillus mostren gran rellevància clínica com a patògens oportunistes que s'associen a gran
varietat de malalties humanes. Entre elles, l'aspergil·losi invasiva és la més severa en termes de morbiditat i mortalitat. Tot i que Aspergillus fumigatus és l'agent causal més comú d'aquesta infecció, recentment s'ha reportat una elevada prevalència clínica d'altres espècies, com els membres de la secció Nigri.
Malgrat que el tractament d'elecció actual per l'aspergil·losi és el voriconazol, la resistència a azols ha augmentat de
manera alarmant, cosa que comporta gran impacte en la gestió de la malaltia. En aquest context, mentre que els
mecanismes de resistència a azols en A. fumigatus han sigut àmpliament estudiats, aquests romanen poc investigats
en espècies no-fumigatus. Per aquests motius, l'objectiu principal d'aquest treball és la caracterització dels mecanismes de resistència a azols en espècies d'Aspergillus de la secció Nigri.
Amb aquest propòsit, s'ha determinat la sensibilitat a azols en aquesta secció i s'han dut a terme anàlisis moleculars i
genètics de les proteïnes diana dels azols, codificades pels gens cyp51. Adicionalment, s'han investigat els continguts
d'ergosterol i les propietats de la membrana plasmàtica i la paret fúngica. Finalment, s'han evaluat potencials
mecanismes de resistència relacionats amb la degradació del fàrmac i l'associació entre resistència a azols i fagocitosi in vitro.
Els nostres resultats mostren diferències amb el que s'ha descrit en A. fumigatus, evidenciant la complexitat dels mecanismes de resistència, especialment en espècies no-fumigatus d'Aspergillus.Algunas especies de Aspergillus muestran relevancia clínica como patógenos oportunistas asociándose a gran variedad de enfermedades humanas. Entre ellas, la aspergilosis invasora es la más severa en términos de morbididad y mortalidad. A pesar de que Aspergillus fumigatus es el agente causal más común de esta infección, recientemente se ha reportado una elevada prevalencia clínica de otras especies, como los miembros de la sección Nigri. Aunque el tratamiento de elección actual para la aspergilosis es el voriconazol, la resistencia a azoles ha aumentado de manera alarmante, lo que conlleva gran impacto en la gestión de la enfermedad. En este contexto, mientras los mecanismos de resistencia a azoles en A. fumigatus han sido extensamente estudiados, éstos permanecen poco investigados en especies no-fumigatus. Por ello, el objetivo principal de este trabajo es la caracterización de los mecanismos de resistencia a azoles en especies de Aspergillus de la sección Nigri. Con este propósito, se ha determinado la sensibilidad a azoles en esta sección y se han llevado a cabo análisis moleculares y genéticos de las proteínas diana de los azoles, codificadas por los genes cyp51. Además, se han investigado los contenidos de ergosterol y las propiedades de la membrana plasmática y la pared fúngica. Finalmente, se han evaluado potenciales mecanismos de resistencia relacionados con la degradación del fármaco y la asociación entre resistencia a azoles y fagocitosis in vitro. Nuestros resultados difieren de aquello descrito en A. fumigatus, evidenciando la complejidad de los mecanimos de resistencia, especialmente en especies no-fumigatus de Aspergillus.
Several species of Aspergillus display clinical relevance, since they are opportunistic pathogens associated to a broad variety of human conditions. Among these, invasive aspergillosis is the most severe in terms of morbidity and mortality. Although Aspergillus fumigatus is the most common causal agent of invasive disease, elevated prevalence of species from other sections, such as section Nigri members, has been reported lately in the clinical field. Despite the current treatment of choice for aspergillosis is voriconazole, azole resistance events have alarmingly increased in the last years, critically impairing disease management. In this context, whereas azole resistance mechanisms in A. fumigatus have been extensively studied, azole resistance in non-fumigatus species remains poorly investigated. On this basis, we aimed to characterize azole resistance in species of Aspergillus section Nigri. With this purpose, we have determined azole susceptibility in section Nigri strains, and we have carried out molecular and genetic analyses of the azoles target proteins, encoded by the cyp51 genes. In addition, ergosterol content and properties of plasma membrane and cell wall have been investigated. Finally, potential resistance mechanisms related to drug degradation and the association between azole resistance and in vitro macrophage phagocytosis were evaluated. Our results diverge from those described in A. fumigatus, which evidences the complexity around resistance mechanisms, especially in non-fumigatus species of Aspergillus.
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Parker, Stephen R. "Sterol biosynthesis in Aspergillus and its inhibition by azole antimycotics." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307142.
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Fowler, Jonathan Michael. "Multimetallic azole and carbene complexes in supramolecular chemistry and catalysis." Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/20912/.
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The development of tritopic azole ligands tethered to the cyclotriveratrylene (CTV) molecular host is described within this thesis. The assembly of tripodal pyridyl-CTV ligands with metal precursors has led to the discovery of a diverse range of metallo-supramolecular assemblies, but comparable ligands incorporating five-membered ring counterparts are considerably less developed. New azole ligands could potentially coordinate to metals at different bite angles compared to the established pyridyl systems, leading to the assembly of previously inaccessible architectures. Furthermore, azoles, in particular 1,3-diazoles, are precursors to organometallic N-heterocyclic carbene (NHC) complexes. The fusion of NHC ligands and CTV cavitands has not previously been investigated. A tritopic benzimidazole ligand was prepared, which assembles with [Pd(Cl)2(MeCN)2] to yield a rare trans-linked metallocryptophane as an alternative to the more commonly encountered architectures requiring a cis-protected Pd(II) precursor. Additionally, the coordination of an oxazole ligand was investigated, leading to the assembly of 1D polymer chains. The assembly of a 4-thiazolyl ligand with AgBF4 and AgReO4 led to the assembly of the first CTV-type coordination cubes, with chiral self sorting upon coordination to Ag(I) and spontaneous resolution of crystals being exhibited. In addition to cubic cages, 2D and 3D coordination polymers were also accessible upon coordination to Ag(I). The first metal-NHC complexes on a CTV scaffold were also prepared, with Ir(III) and Ru(II) complexes being examined as catalysts in the transfer hydrogenation of acetophenone, suggesting that in the case of Ru(II), intermolecular cooperativity may be exhibited. Trinuclear Pd(II)-NHC complexes were targeted, and examined as catalysts in the regioselective Suzuki-Miyaura reaction of 2,4-dibromopyridine and 4-methoxybenzeneboronic acid. Catalysts displayed high activities over a short period of time, preparing traces of the ‘favoured’ o-coupled product and significant quantities of para- and bis-coupled products, potentially via two pathways.
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Bueid, Ahmed. "Laboratory epidemiology and mechanisms of azole resistance in Aspergillus fumigatus." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/laboratory-epidemiology-and-mechanisms-of-azole-resistance-in-aspergillus-fumigatus(cfaa6ee2-36d5-473c-9531-816d9578ff17).html.
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Although A. fumigatus strains are generally susceptible to azoles, recently, acquired resistance to a number of antifungal compounds has been reported, especially to triazoles possibly due to widespread clinical use of triazoles or through exposure to azole fungicides in the environment. The significant clinical problem of azole resistance has led to study the antifungal resistance mechanisms for developing effective therapeutic strategies. Of 230 clinical A. fumigatus isolates submitted during 2008 and 2009 to the Mycology Reference Centre Manchester, UK (MRCM), 64 (28%) were azole resistant and 14% and 20% of patients had resistant isolates, respectively. Among the resistant isolates, 62 of 64 (97%) were itraconazole resistant, 2 of 64 (3%) were only voriconazole resistant and 78% were multi-azole resistant. The gene encoding 14-α sterol demethylase (cyp51A) was analyzed in 63 itraconazole resistant (ITR-R) and 16 ITR-susceptible clinical and environmental isolates of A. fumigatus respectively. Amino acid substitutions in the cyp51A, the commonest known mechanism of azole resistance in A. fumigatus, were found in some ITR-R isolates. Fifteen different amino acid substitutions were found in the cyp51A three of which, A284T, M220R and M220W, have not been previously reported. In addition, several mutations were found in the cyp51A gene in one of the A. fumigatus environmental isolates. Importantly, a remarkably increased frequency of azole-resistant isolates without cyp51A mutations was observed in 43% of isolates and 54% of patients. Other mechanisms of resistance must be responsible for resistance. In order to assess the contribution of transporters and other genes to resistance, particular resistant isolates that did not carry a cyp51A mutation were studied. The relative expression of three novel transporter genes; ABC11, MFS56 and M85 as well as cyp51A, cyp51B, AfuMDR1, AfuMDR2 AfuMDR3, AfuMDR4 and atrF were assessed using real-time RT-PCR in both azole susceptible and resistant isolates, without cyp51A mutations. Interestingly, deletion of ABC11, MFS56 and M85 from a wild-type strain increased A. fumigatus susceptibility to azoles and these genes showed changes in expression levels in many ITR-R isolates. Most ITR-R isolates without cyp51A mutations showed either constitutive high-level expression of the three novel genes or induction of expression upon exposure to itraconazole. One isolate highly over-expressed cyp51B, a novel finding. Our results are most consistent with over-expression of one or more of these genes in ITR-R A. fumigatus without cyp51A mutations being at least partially responsible for ITR resistance. Multiple concurrent possible resistance mechanisms were found in some isolates. My work probably explains the mechanism(s) of resistance in A. fumigatus isolates with cyp51A mutations. Other ITR resistance mechanisms are also possible. To determine taxonomic relationships among A. fumigatus clinical and environmental isolates, the sequences of the ITS, β-tubulin, actin and calmodulin gene of 23 clinical and 16 environmental isolates were analyzed phylogenetically. Actin and calmodulin sequences proved to be good for species differentiation of A. fumigatus while both ITS, β-tubulin regions did not, in this dataset. Many cryptic species of A. fumigates (complex) were found. All environmental A. fumigates complex isolates were ITR susceptible and no cross resistance was found.
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Mancini, Riccardo. "Inverse and regular phenyl-azole ligands for luminescent Iridium(III) complexes." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amslaurea.unibo.it/9318/.
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In the modern society, light is mostly powered by electricity which lead to a significant increase of the global energy consumption. In order to reduce it, different kinds of electric lamps have been developed over the years; it is now accepted that phosphorescence-based OLEDs offer many advantages over existing light technologies. Iridium complexes are considered excellent candidates for bright materials by virtue of the possibility to easily tune the wavelength of the emitted radiation, by appropriate modifications of the nature of the ligands. It is important to note that the synthesis of Ir(III) blue-emitting complexes is a very challenging goal, because of wide HOMO-LUMO gaps needed for produce a deep blue emission.
During my thesis I planned the synthesis of two different series of new Ir(III) heteroleptic complexes, the C and the N series, using cyclometalating ligands containing an increasing number of nitrogens in inverse and regular position. I successfully performed in the synthesis of the required four ligands, i.e. 1-methyl-4-phenyl-1H-imidazole (2), 4-phenyl-1-methyl-1,2,3-triazole (3), 1-phenyl-1H-1,2,3-triazole (6) and 1-phenyl-1H-tetrazole (7), that differ in the number of nitrogens present in the heterocyclic ring and in the position of the phenyl ring. Therefore the cyclometalation of the obtained ligands to get the corresponding Ir(III)-complexes was attempted. I succeeded in the synthesis of two Ir(III)-complexes of the C series, and I carried out various attempts to set up the appropriate reaction conditions to get the remaining desired derivatives. The work is still in progress, and once all the desired complexes will be synthesized and characterized, a correlation between their structure and their emitting properties could be formulated analysing and comparing the photophysical data of the real compounds.
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Stephen, Jennifer Lea. "Studies towards the decarboxylative cross-coupling of azole-4-carboxylic acids." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/18011.
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Some interesting, biologically active natural products have been found to contain poly-azole fragments within their core. These fragments are linked through the 2- position of one azole and the 4-position of its neighbour. Decarboxylative cross-coupling methodology may provide a route to these desired linked azoles through cross-coupling of azole-4-carboxylic acids with azole-2- halides or with azoles containing no substitution at the 2-position. Investigations into the silver-mediated decarboxylation, and subsequent coupling potential, of thiazole and oxazole-4-carboxylic acids are reported. Methods towards the synthesis of novel chlorinated thiazole and oxazole acids and their precursors are also described. A method to successfully couple these acids to aryl iodides has been developed and the scope of this reaction extended to a variety of functionalised azole-4-carboxylic acids. Attempts to extend this methodology and combine the decarboxylative coupling with CH activation of a second azole are also described.
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CIANCIMINO, Cristina. "Synthesis of Azole-Heterocycles as Potential Antitumor and/or Antiviral Agents." Doctoral thesis, Università degli Studi di Palermo, 2014. http://hdl.handle.net/10447/90986.
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Ballard, S. A. "Interaction of azole antifungal agents with mouse hepatic microsomal cytochromes P-450." Thesis, University of Kent, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383094.
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Wright, James. "Guest entrapment, uptake and release in metal-azole based frameworks and complexes." Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/12153/.
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The work in this thesis is generally concerned with the crystal engineering of azole or azolate containing coordination compounds, either in molecular clusters or within metal-organic frameworks. The intermolecular interactions that halogenated azole/azolate coordination compounds are capable of supporting in the solid state are explored. The functionality of molecular materials and metal-organic frameworks containing azole/azolates is also examined.
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Abdelhameed, Ahmed M. "THE DESIGN AND SYNTHESIS OF CYANINES AND ARYLIMIDAMIDE AZOLE HYBRIDS AS ANTILESIHMANAIAL AGENTS." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1525738213459762.
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Kamai, Yasuki. "Studies on azole resistance and virulence of Candida albicans, and novel antifungal agents." Kyoto University, 2004. http://hdl.handle.net/2433/145438.
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Kyoto University (京都大学)0048
新制・論文博士
博士(農学)
乙第11557号
論農博第2544号
新制||農||901(附属図書館)
学位論文||H16||N3980(農学部図書室)
22817
UT51-2004-T201
(主査)教授 植田 和光, 教授 加藤 暢夫, 教授 植田 充美
学位規則第4条第2項該当
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Johnson, E. M. "In vitro effects of antifungal drugs on Candida albicans and phagocytic cell function." Thesis, University of Bristol, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375031.
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Joshi, Madhur Satish. "Elaboration of azine and azole anhydrobases via intra- and intermolecular cyclizations for heterocycle construction." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5788.
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Aza-heterocycles such as pyridines, imidazoles, piperidines, etc. are ubiquitous structural motifs found in various natural products and pharmacologically active compounds. Thus, they are of unparalleled importance to synthetic, medicinal, and materials chemists. Despite their structural significance, organic transformations available for the functionalization of these heterocycles remain underdeveloped. The development of several synthetic methods to construct aza-heterocyclic building blocks is described in this thesis, which, in turn, should facilitate the assembly of more elaborate frameworks present in bioactive molecules.
An intramolecular palladium catalyzed Mizoroki-Heck cyclization of 4-alkylidene dihydropyridines with tethered aryl iodide electrophiles is demonstrated. This provides access to substituted isoindolinones and oxindoles in high yields. An asymmetric variant of this reaction using chiral phosphine ligands delivers enantioenriched oxindoles and isoindolinones. Additionally, an intramolecular Mizoroki-Heck reaction for the synthesis of 2-substituted pyridine derivatives is also developed. An array of fused isoindolinones is constructed as a mixture of diastereomers and further manipulated using chemical transformations to yield the corresponding pyridine and piperdine derivatives.
Moreover, a formal [3+2] cyclocondensation of alkylidene dihydropyridines and aryl diazonium salts has been discovered for the synthesis of triazole derivatives. Tertiary amides deliver substituted 1,2,4-triazolium salts, whereas, secondary amides provide substituted, neutral 1,2,4-triazoles in excellent yields, under mild reaction conditions.
Furthermore, an intramolecular direct arylation of 2- and 4-substituted alkylpyridines is developed for the synthesis of 2,3- and 3,4-cyclized pyridines. It is shown that 4-alkylpyridines tethered to aryl halides participate in a palladium catalyzed direct arylation to give fused 7-membered lactams in excellent yields.
Lastly, an intramolecular cyclization of 1,2-alkylimidazoles is reported. Alkylidene imidazolines tethered to electrophilic keto-amide sidechains participate in an aldol-like reaction to yield γ-lactam products in good yields as mixtures of diastereomers.
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Uch, Antje Sabine. "Intestinal uptake of azole antifungals in rats : method development, validation and determination of uptake mechanisms /." Aachen : Shaker, 1999. http://www.gbv.de/dms/bs/toc/312097247.pdf.
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Ghazal, Heba. "The impact of biorelevant media on the in-vitro dissolution of azole anti-fungal drugs." Thesis, Liverpool John Moores University, 2009. http://researchonline.ljmu.ac.uk/5943/.
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Cormier, Virginie. "Etude des données actuelles concernant la résistance aux antifongiques azoles dans les candidoses." Paris 5, 2001. http://www.theses.fr/2001PA05P015.
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Talbot, Jessica Jane. "Common and cryptic Aspergillus species – one health pathogens." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/19930.
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Fungal Aspergillus species cause invasive and chronic disease in humans and other animals. This thesis investigated cryptic and common Aspergillus species in A. section Fumigati; their prevalence in Australia and virulence factors impacting the efficacy of the most commonly used antifungal drugs, triazoles. An environmental (soil and air) investigation of 104 Aspergillus isolates for cryptic A. sect. Fumigati species, focusing on the A. viridinutans species complex (AVSC), found a moderate risk of exposure to known pathogenic and cryptic species, but low risk AVSC exposure in indoor and outdoor domestic environments. A new AVSC species was discovered, A. frankstonensis (morphology; ITS region, BenA, CalM, MCM7, actin and RPB2 gene sequencing; antifungal susceptibility; and extrolite analysis are described). Sequencing (ITS, BenA) of clinical isolates from captive birds (n=30) identified A. fumigatus as the most common cause of disease and A. restrictus as pathogenic. Triazole resistance amongst A. fumigatus isolates from clinical and environmental samples is documented over two studies, identifying a low prevalence in Australia. The first investigated pathogenic A. fumigatus isolates from dogs and cats (n=50), finding triazole resistance in one Australian isolate from a dog in the early 1990’s (Sensititre™ YeastOne™YO8). The second investigated clinical (148 human, 21 veterinary) and environmental (n=185) Australian isolates (VIPcheck™ and Sensititre™ YeastOne™ YO10), confirming triazole resistance in three human origin isolates, associated with cyp51A mutations TR34/L98H and G54R. Triazole susceptibility (CLSI) of 37 AVSC isolates were investigated, detecting high triazole minimum inhibitory concentrations (84% of isolates). Compared to wild-type A. fumigatus, high rates of cyp51A mutations were detected on sequencing; however protein homology modelling did not confer resistance. This research informs our understanding of A. sect. Fumigati pathogens in Australia.
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Tsao, Tan Ning. "Chemotherapy of candidiasis: study of ABC transporter- mediated azole resistance and identification of a novel antifungal therapeutic strategy." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103634.
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Candida albicans is a major fungal pathogen that causes systemic bloodstream infections with high mortality rate in immune-compromised patients. Current treatment of candidiasis involves the use of azoles (the most widely used antifungal agents that target ergosterol biosynthesis) and echinocandins (the latest approved drugs that target cell wall). However, the efficacy of these drugs can be compromised by the emergence of C. albicans drug-resistant strains. Thus, understanding the molecular mechanisms of azole resistance as well as identifying new biological targets are important for the development of novel and effective therapeutic strategies. In this thesis, I report our research findings on the contribution of ABC transporters Cdr1p and Cdr2p to azole resistance in a clinical azole resistant strain and show that Cdr1p is a major determinant of azole resistance. Furthermore, we also discovered that phosphorylation plays a positive regulatory role on Cdr1p function and is important for Cdr1p-mediated azole resistance. In an effort to search for new antifungal targets, we explored the function of genes involved in the acetylation of histone H3 lysine 56 (H3K56) in C. albicans. We found that the gene encoding H3K56 deacetylase Hst3p is essential for cell growth and survival of C. albicans. Inhibition of Hst3p using nicotinamide, a form of vitamin B3, is fungicidal for both drug-susceptible and drug-resistant C. albicans as well as another important human fungal pathogen Aspergillus fumigatus, making it a promising target to develop a novel class of antifungal agents with broad antifungal properties. Taken together, these studies provide fundamental knowledge of molecular determinants contributing to C. albicans azole resistance and pathogenesis.Candida albicans est un pathogène fongique responsable d'infections systémiques dont le taux de mortalité est élevé chez les patients immunocompromis. À l'heure actuelle, le traitement de la candidose est rendu possible par l'utilisation de deux classes d'agents antifongiques aux modes d'actions distincts : les azoles (les plus couramment utilisés, ils ciblent la biosynthèse de l'ergostérol) et les échinocandines (nouvellement mises sur le marché, elles interfèrent avec la synthèse de la paroi fongique). Toutefois, face à l'émergence de résistances développées par certaines souches de C. albicans l'efficacité de ces antifongiques se trouve compromise. Il est donc capital de mieux comprendre les mécanismes moléculaires impliqués dans la résistance aux azoles, ainsi que d'identifier de nouvelles cibles biologiques pour permettre le développement d'approches thérapeutiques innovantes et efficaces. Dans ce manuscrit de thèse, je décris nos travaux portant sur la contribution relative des transporteurs ABC Cdr1p et Cdr2p à la résistance aux azoles en utilisant une souche clinique résistante de C. albicans, et démontre que Cdr1p contribue majoritairement à cette résistance. D'autre part, nous montrons que la phosphorylation a un effet positif sur la régulation de Cdr1p, et également que cette modification post-traductionnelle joue un rôle important dans la résistance aux azoles Cdr1p-dépendante. Dans l'optique d'identifier de nouvelles cibles antifongiques, nous avons étudié la fonction des gènes impliqués dans l'acétylation de la lysine 56 de l'histone H3 (H3K56) chez C. albicans. Nous avons découvert que le gène codant pour la déacétylase de H3K56, à savoir Hst3p, est essentiel pour la survie et la croissance cellulaire chez C. albicans. L'inhibition de Hst3p par la nicotinamide, une forme de vitamine B3, a un effet fongicide sur de multiples souches de C. albicans, qu'elles soient normales ou résistantes aux médicaments, ainsi que sur un autre pathogène important chez l'humain, Aspergillus fumigatus, faisant de cette enzyme une cible prometteuse pour le développement de nouveaux agents antifongiques à large spectre. L'ensemble des connaissances fondamentales générées au cours de mes travaux de doctorat permettra de mieux comprendre certains déterminants moléculaires clés qui contribuent à la résistance de C. albicans envers les médicaments azolés, ainsi qu'à sa pathogénicité.
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Fernandez, Christine Cheryl. "Characterisation of cytochrome P450 azole drug-resistant sterol demethylase CYP51B1 and expression of CYP123 and CYP136 from Mycobacterium tuberculosis." Thesis, University of Manchester, 2011. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:171502.
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Tuberculosis (TB) affects nearly a third of the world’s population and has been termed a ‘Global Emergency’ by the WHO. The emergence of multi/extensively drug resistant (M/XDR) strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB, and the increasing incidences of azole drug resistant sterol demethylases (CYP51) from pathogenic fungi has propelled studies to understand mechanisms of azole drug resistance on the drug target CYP51. Since Mtb is devoid of a sterol biosynthetic pathway, the presence and study of CYP51B1 and 19 other Cytochrome P450s in its genome is important to clarify host-pathogen mechanism of infection and the potential of using azole drugs to treat TB. In this study, CYP51B1 from Mtb was used as the model enzyme to study CYP51 mutants from Candida albicans fluconazole-resistant clinical strains. By protein engineering methods, F89H, L100F, S348F, G388S and R391K CYP51B1 mutants were made and azole drug binding properties were investigated using stopped-flow kinetics and static equilibrium methods. Dissociation constant (Kd) values were derived for a range of commercially available azole drugs by fitting the equilibrium binding data to a hyperbolic equation. Kd values for stopped-flow kinetics were derived by plotting observed binding rates (kobs) across different azole drug concentrations against time, followed by fitting multiple kobs data to a linear equation to derive azole drug de-binding (koff) and binding (kon) rate constants – the Kd was obtained by koff/kon. Extinction coefficient for heme b content in mutants and Wild Type (WT) CYP51B1 were an average of ɛ419 = 96.1 mM-1 cm-1. Biochemical characterisation of the mutants were carried out using established experiments on CYP51 – reduction of Fe(III)-heme to Fe(II)-heme, NO binding to Fe(III)-heme, rates of CO-Fe(II) adduct formation and rates of collapse of the P450 to P420 species in the presence of CO and estriol with redox partners from Mtb. In order to elucidate the effects of the above mutations on the iron-heme catalytic region, electron paramagnetic resonance (EPR) experiments were carried out with and without azole drugs. Circular dichroism (CD), differential scanning calorimetry (DSC) and multi-angled laser light scattering (MALLS) analysis confirmed that F89H, R391K and L100F mutants were stable and homogeneous. Crystallogenesis was successful for the above mentioned mutants and atomic structures were obtained for all mutants and WT CYP51B1 (in ligand-bound and substrate-free forms), except for S348F and G388S mutants which were expressed as inclusion bodies and 60% holoenzyme, respectively. Reconstituted catalytic assays to determine the sterol demethylating propensity of the mutants were carried out using redox partners from Mtb or E. coli, and with lanosterol and dihydrolanosterol as the surrogate substrates. Redox potentiometry showed similar potentials to WT for all mutants except for the G388S mutant which was relatively positive (–102 mV). Redox cycling experiments followed by EPR analysis for mutants and WT resulted in a novel P450 high-spin species at g value 5.84 (80 %) which gradually collapsed to the initial low spin state over 48 h. Expression trials were concurrently carried out on two other Mtb P450 genes – CYP123 (Rv0744c) and CYP136 (Rv3059) products of which may have similar functions to CYP51B1 or may share similar redox partners. CYP123 is located on the same operon as CYP51B1 while CYP136 has a 29% sequence identity to another CYP51 from a marine slime bacterium. Although further work is necessary, in this study CYP123 was expressed totally as inclusion bodies while CYP136 was expressed as soluble apoprotein fused with trigger factor chaperone.
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El, Hammi Emna. "Les flavohemoglobines comme cibles potentielles des antibiotiques." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112051.
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Les flavohémoglobines (FlavoHbs) sont des protéines fixant l’oxygène qui possèdent un domaine globine N-terminal lié de manière covalente à un domaine C-terminal réductase contenant une flavine adénine dinucléotide (FAD) et un site de fixation du nicotinamide adénine dinucléotide (phosphate) (NAD(P)H). Ces protéines que l’on retrouve exclusivement chez les microorganismes possèdent une action NO dioxygénase et interviennent donc dans la défense des microorganismes contre les dommages générés par le NO. De par ce rôle essentiel de défense microbienne, les flavoHbs sont considérés comme des cibles attractives des antibiotiques. En particulier, les dérivés azolés ont montré la capacité d’inhiber la fonction NO dioxygénase des flavoHbs par un mécanisme inconnu. Afin de mieux comprendre le mode d’action de ces antibiotiques, nous avons entrepris une étude structurale, enzymatique et spectroscopique sur trois flavoHbs d’intérêt. Les structures tridimensionnelles de la flavoHb de R. eutropha (FHP) en complexe avec le miconazole, l’éconazole et le kétoconazole ainsi que celle de S. cerevisae (YHB) seule et en complexe avec l’éconazole ont été obtenues à des résolutions satisfaisantes permettant de décrire précisément les interactions entre la protéine et les inhibiteurs. Les structures ont révélé des réarrangements conformationnels importants selon la nature chimique de l’inhibiteur et la présence d’acides gras dans la poche de l’hème. Afin de comprendre le rôle fonctionnel des acides gras dans le cycle catalytique de l’enzyme, la structure tridimensionnelle de la FHP en complexe avec l’acide linolénique a été obtenue et des analyses enzymatiques et spectroscopiques ont montré l’importance des acides gras dans la modulation de l’activité de la protéine. Parallèlement, des études sur la FHP, la YHB et la flavoHb de S. aureus (Shb) ont permis de mieux appréhender le rôle des inhibiteurs dans le processus de transfert d’électrons au sein de la protéineFlavohemoglobins (FlavoHbs) are oxygen binding proteins which consist of a heme-globin domain fused with a ferredoxin reductase –like FAD and NAD-binding domain. FlavoHbs have been identified exclusively in microorganisms where they play a key role in defence against NO damages by using their NO dioxygenase activity. These proteins are therefore considered as targets for new antibiotic drugs. Recently, azole derivatives were proven to be attractive nitric oxide dioxygenase inhibitors by a mechanism that remains elusive. In order to explore their binding characteristics, we determined the X-ray structure of the flavoHb from Ralstonia eutropha in a complex with miconazole (FHPm), econazole (FHPe), and ketoconazole (FHPk) as well as the X- ray structure of S. cerevisae flavoHb in both ligand-free and econazole-bound forms. We describe the interactions between the protein matrix and the inhibitors in a comparative manner and how the bulky structures of the azole inhibitors dictate the profile of the hemebinding pocket and vice versa in flavoHbs.Although the azole compounds were able to push the lipid out of its binding site, a fatty acid fragment is still bound inside the heme pocket of FHPe and FHPk and dictates the state of the protein. To go further in the compréhension of the fatty acid function in the flavoHbs, we determined the three dimensionnal structure of FHP in complex with linolenic acid. Spectroscopic and enzymatic analyzis confirmed the important role of fatty acids in enhancing the protein activity. We also made studies to understand how azoles modulate the electron transfer process in the flavoHbs
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Malaviarachchige, Rabel Ranga P. "A study of the structure-property relationship of azole-azine based homoleptic platinum(II) complexes and tunability of the photo-physical properties." Thesis, University of Surrey, 2016. http://epubs.surrey.ac.uk/809757/.
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Owing to superior energy efficiency, Light Emitting Diode (OLED) technology has become considerably commercialised over the last decade. Innovations in this field have been spurred along by the discovery of new molecules with good stability and high emission intensity, followed through by intense engineering efforts. Emissive transition metal complexes are potent molecular emitters as a result of their high quantum efficiencies related to facile intersystem crossing (ISC) between excited-state manifolds (efficient spin orbit coupling (SOC)) and resultant efficient emission from the triplet state (phosphorescence). These also allow rational tuning of the emission wavelengths. Tuning of the ground and excited state energies, and thus emission wavelength of these complexes can be achieved by subtle structural changes in the organic ligands. Pyridyl-triazole ligands have started receiving increasing attention in recent years as strong field ligands that are relatively straightforward to synthesise. In this study we explore the emission tunability of a newly synthesised series of 5-subsituted-Pyridyl-1,2,3-triazole-based ligands and their Pt(II) complexes. Studies have shown, substitution at the triazole moiety is less effective in achieving emission tunability. Alternatively we carried out the substitution at the 5th position of the pyridine ring with a wide range of electronically diverse, donor-acceptor groups (-N(CH3)2, -H, -CHO, -CHC(CN)2). The target ligands were approached through the serial application of the Sonogashira carbon–carbon coupling and the Sharpless copper-catalyzed Huisgen’s 1,3-dipolarcycloaddition procedures. As a result, coarse tunability of excimer emission was observed in thin-films, generating blue-(486 nm), green-(541 nm), orange-(601 nm) and red-(625 nm) luminescence respectively. This “turned-on” substituent effect was accounted for metallophilic Pt—Pt interaction-induced aggregates in the solid state. Excited state calculations reveal that the solid state emission is associated with 1MMLCT transitions. Lifetime measurements revealed the existence of two decay processes: one being fluorescence and the other process, either phosphorescence or delayed fluorescence. Further a linear-relationship between the Hammett parameters of the substituents and emission wavelengths was established. This allows a reliable emission predictability for any given substituent of 5-substituted pyridyl-1,2,3-triazole platinum complexes. In conclusion, we show a new approach in achieving coarse emission tunability in pyridyl-1,2,3-triazole based platinum complexes via subtle changes in the molecular structure and the importance of metallophilic interactions in the process. During the second phase of the study, the scope was broadened to examine the effects of heterocyclic nitrogens in the ligand skeleton. Fifteen different combinations of azole-azine linked ligand systems were synthesized, by systematically increasing the number of nitrogens and changing the ring position of the nitrogens in the skeleton. Later, the homoleptic platinum complexes of the respective ligands were synthesised, and the photo-physical characteristics were studied. The above mentioned changes in the ligand structure resulted in a 264 nm emission tunability, in the thin films of the complexes. Theoretical studies on the complexes revealed that based on the structure of the ligand, different metallophilic stacking behaviours and different origins of emission (fluorescence and phosphorescence) can result, which in turn give rise to tunable emission wavelengths.
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Potgieter, Wilna. "An investigation of the possible anticancer activity of seven novel bi(amido) gold(I) complexes derived from a purine or azole base." Diss., Pretoria : [s.n.], 2009. http://upetd.up.ac.za/thesis/available/etd-09112009-155357/.
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Beijer, Kristina. "Azoles and Contaminants in Treated Effluents Interact with CYP1 and CYP19 in Fish :." Doctoral thesis, Uppsala universitet, Miljötoxikologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-251295.
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Numerous contaminants are present in mixtures in the aquatic environment. Among these are the azoles, a group of chemicals that includes both pharmaceuticals and pesticides. Azole fungicides are designed to inhibit lanosterol 14-demethylase (cytochrome P450 (CYP) 51), while other azoles are intended to inhibit aromatase (CYP19), i.e. the enzyme catalyzing biosynthesis of estrogens. In fish, a variety of CYP enzymes are involved in biotransformation of waterborne contaminants, and in metabolism of endogenous compounds including steroidal hormones. The induction of CYP1A protein and 7-ethoxyresorufin O-deethylase (EROD) activity are common biomarkers for exposure to aryl hydrocarbon receptor (AhR) agonists in fish. We developed an assay to measure inhibition of CYP1A activity (EROD) in three-spined stickleback and rainbow trout gill tissue ex vivo. Several azole fungicides were found to be potent inhibitors of CYP1A activity. A wastewater effluent containing high concentrations of pharmaceuticals was also shown to inhibit CYP1A activity. Further, several azoles inhibited CYP19 activity in rainbow trout brain microsomes in vitro. Azole mixtures reduced both CYP1A and CYP19 activity monotonically and in an additive way. Given the additive action of the azoles, studies to determine adverse effects of azole mixtures on CYP-regulated physiological functions in fish are needed. Induction of EROD and of gene expression of CYP1 in several organs was observed in an in vivo exposure with the same effluent shown to inhibit EROD. This finding could imply that there was a mixture of AhR agonists and CYP1A inhibitors in the effluent. Finally, wastewater treatment technologies were evaluated using biomarker responses in rainbow trout exposed to effluents of different treatments. The results from chemical analysis together with the biomarker results show that ozone and granulated active carbon treatment removed most pharmaceuticals, as well as AhR agonists and other chemicals present in the regular effluent. This part of the thesis demonstrates that biomarkers in fish such as induction of CYP1 gene expression are applicable to evaluate the efficiency of different treatment technologies for wastewater.
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Campagne, Benjamin. "Nouveaux copolymères fluorés porteurs de fonctions azole (imidazole, benzimidazole ou triazole) pour membranes pour piles à combustible (PEMFC) fonctionnant en conditions quasi-anhydres." Thesis, Montpellier, Ecole nationale supérieure de chimie, 2013. http://www.theses.fr/2013ENCM0006.
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Ce travail de thèse s'inscrit dans la continuité des travaux de recherche sur l'utilisation d'hétérocycles azotés pour l'élaboration de membranes échangeuses de protons pour piles à combustible de type PEMFC fonctionnant sous faible taux d'humidité relative (HR < 25 %) et à des températures allant jusqu'à 200 °C pour l'application automobile. Pour cela, trois nouveaux copolymères partiellement fluorés porteurs de trois groupements azole (imidazole, benzimidazole et 1H-1,2,4-triazole) ont été synthétisés et caractérisés. Ils ont ensuite été utilisés pour l'élaboration de membranes polymères (20 µm < épaisseurs < 100 µm) par mélange avec le s-PEEK. Ces membranes sont stables thermiquement jusqu'à 210 °C. Les trois séries de membranes ont été comparées et les meilleurs résultats de conductivité protonique ont été obtenus pour celles contenant le 1H-1,2,4-triazole (σ = 7,0 mS.cm-1, 140 °C, HR < 25 %). Les propriétés mécaniques de ces membranes ont été mesurées et ont montré des valeurs comparables à celles des principales membranes commerciales (de type Nafion®). Afin d'obtenir une meilleure structuration de ces membranes, une stratégie d'élaboration de pseudo réseaux semi-interpénétrés de s-PEEK dans un réseau polymère réticulé a été mise au point. Pour cela, de nouveaux terpolymères porteurs de groupements 1H-1,2,4-triazole et de groupements cyclocarbonate réticulables par la réaction cyclocarbonate / amine ont été synthétisés et caractérisés. Ces terpolymères ont été mélangés à du s-PEEK puis réticulés par une diamine pour former des pseudo réseaux semi-interpénétrés de faibles épaisseurs (20 µm < e < 60 µm) qui ont été caractérisés. Ces membranes à architecture pseudo réseaux semi-interpénétrés ont montré de meilleures propriétés mécaniques mais des valeurs de conductivité protonique légèrement inférieures à celles des membranes non réticulées. Enfin, les membranes réticulées ou non ont été dopées par l'acide phosphorique pour augmenter leurs valeurs de conductivité protonique. Des essais en mono-cellule de PAC de ces membranes dopées ont été effectués et ont montré de bonnes performances. Des estimations par extrapolations des résultats ont ensuite été effectuées à plus hautes températures (140 – 200 °C) et ont montré que les valeurs de conductivité protonique atteignent jusqu'à 210 et 250 mS.cm-1, à 180 et 200 °C, HR < 25 % (valeurs extrapolées). Ces valeurs extrapolées doivent être vérifiées par la réalisation de mesures de conductivité protonique à ces températures (140 – 200 °C)This work concerns the syntheses and characterizations of new proton exchange polymer membranes containing N-heterocyclic compounds for PEMFC working under low relative humidity (HR < 25 %) and temperatures up to 200 °C for automotive applications. Three new partially fluorinated copolymers bearing different azole compounds (imidazole, benzimidazole or 1H-1,2,4-triazole) as pendant groups have been synthesized and characterized. Then, they have been used to synthesize blend polymer membranes with s-PEEK (20 µm < thickness < 100 µm) that showed thermal stabilities up to 210 °C. These new families of membranes have been compared and highest proton conductivity values have been observed for 1H-1,2,4-triazole containing membranes (σ = 7,0 mS.cm-1, 140 °C, HR < 25 %). Mechanical properties and oxidative stability of these membranes have been assessed and showed similar values than main commercially available membranes. To improve membranes structuration, pseudo semi-interpenetrating polymer networks have been synthesized. Thus, original cross-linkable terpolymers bearing 1H-1,2,4-triazole and cyclocabonate functions as pendant groups have been synthesized and blended with s-PEEK as linear polymer to synthesize new polymers membranes (20 µm < thickness < 60 µm). Cross-linking has been carried from the cyclocarbonate/diamine reaction to get pseudo semi-interpenetrated polymer networks. Finally, both pseudo semi-interpenetrated polymer networks and uncross-linked membranes were doped by immersion in phosphoric acid solution to increase proton conductivity of these materials. Single cell fuel cell tests have been carried out and showed good performances. High temperatures (140 – 180 °C) proton conductivity values of these doped membranes have been estimated from extrapolation curves and reached up to 210 and 250 mS.cm-1, at 180 and 200 °C, HR < 25 %, respectively (extrapolated values). Proton conductivity values should be assessed at these targeted temperatures (140 to 200 °C)
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Lassalas, Pierrik. "Étude de nouvelles méthodologies d'arylation directe en séries azole et pyridine : Application à la synthèse de coeurs de thiopeptides antibiotiques de la série d." Phd thesis, INSA de Rouen, 2012. http://tel.archives-ouvertes.fr/tel-00857574.
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Face à l'apparition grandissante de souches bactériennes multi-résistantes à l'arsenal d'antibiotiques actuels, les thiopeptides antibiotiques, bien que connus depuis plus de 60 ans, suscitent actuellement un fort regain d'intérêt. En effet, cette classe de molécules présente une forte activité antibiotique contre des souches bactériennes résistantes et multirésistantes, et met en œuvre deux modes d'inhibition originaux de la synthèse protéique encore inexploités en thérapie antibiotique humaine. Leur développement pharmacologique est en particulier freiné par la difficulté de préparation de ces molécules très complexes. L'élaboration d'une stratégie innovante de synthèse de la partie la plus complexe de ces molécules, le cœur hétérocyclique est étudiée dans ce travail. Cette approche repose sur l'étude et la valorisation de nouvelles méthodologies de fonctionnalisation directe des liaisons C-H et C-X de mono- et bis-thiazoles avec une large gamme d'hétéroaromatiques. Sa viabilité est démontrée par la préparation du cœur hétérocyclique commun aux amythiamicines.
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Lassalas, Pierrik. "Étude de nouvelles méthodologies d’arylation directe en séries azole et pyridine : Application à la synthèse de coeurs de thiopeptides antibiotiques de la série d." Thesis, Rouen, INSA, 2012. http://www.theses.fr/2012ISAM0024/document.
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Face à l’apparition grandissante de souches bactériennes multi-résistantes à l’arsenal d’antibiotiques actuels, les thiopeptides antibiotiques, bien que connus depuis plus de 60 ans, suscitent actuellement un fort regain d’intérêt. En effet, cette classe de molécules présente une forte activité antibiotique contre des souches bactériennes résistantes et multirésistantes, et met en œuvre deux modes d’inhibition originaux de la synthèse protéique encore inexploités en thérapie antibiotique humaine. Leur développement pharmacologique est en particulier freiné par la difficulté de préparation de ces molécules très complexes. L'élaboration d'une stratégie innovante de synthèse de la partie la plus complexe de ces molécules, le cœur hétérocyclique est étudiée dans ce travail. Cette approche repose sur l'étude et la valorisation de nouvelles méthodologies de fonctionnalisation directe des liaisons C-H et C-X de mono- et bis-thiazoles avec une large gamme d’hétéroaromatiques. Sa viabilité est démontrée par la préparation du cœur hétérocyclique commun aux amythiamicinesDue to the emergence of multiresistant bacterial strains to standard antibacterial treatments, thiopeptides antibiotics are actually highly considered, though they are known for 60 years. They show an excellent antibiotic activity against multiresistant bacterial strains, and implement two originals inhibition mechanisms of protein synthesis, still unemployed in human therapy. However, the difficulty to prepare these complex macromolecules limits their pharmacological development. The development of a new strategy to synthetize the most complicated part of these macromolecules, their heterocyclic core, is studied here in. This approach is based on the study and the exploitation of novel direct C-H and C-X transition-metal-catalyzed couplings of mono- and bithiazoles units with a broad panel of heteroaromatics. Its viability is here demonstrated trough the multi-step synthesis of the common heterocyclic core of amythiamicins
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Tryono, Reno [Verfasser], Holger B. [Akademischer Betreuer] Deising, Klaus [Akademischer Betreuer] Humbeck, and Andreas von [Akademischer Betreuer] Tiedemann. "Two ABC transporters of the MRP subfamily contribute to azole tolerance and virulence of Fusarium graminearum / Reno Tryono ; Holger B. Deising, Klaus Humbeck, Andreas von Tiedemann." Halle, 2016. http://d-nb.info/1116951576/34.
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Battistoni, M. "DEVELOPMENT OF AN INTEGRATED SYSTEM BIOLOGY MODEL FOR PREDICTING MIXTURES OF CHEMICALS ACTING ON THE SAME PATHWAY." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/489001.
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Exposure of the embryo to environmental chemicals (pesticides, air and water pollutants) can result in congenital malformations or developmental defects such as oro-facial cleftings. Unfortunately, the human embryo is not usually exposed to a single substance, but to many substances simultaneously. Despite the efforts in elucidating mechanism of action (MoA) of substances that perturb the normal embryonic development, only a small part of involved pathways have been understood to date (Giavini and Menegola, 2004). This is why, evaluating the toxicity of mixtures of multiple chemicals is one of the major objectives of today’s toxicology despite the effect of exposure to a mixture is still difficult to understand. To arrive in the future to the creation of a realistic overall picture of human exposure to mixtures, the development of integrated approaches between in vitro and in silico techniques and computational systems biology, able to predict the effects of mixtures starting from the concentrations of their individual components, will be essential. Recent studies suggest that the similarity of molecular initiating events (MIEs) is not an essential requirement to induce additive effects, because mixtures composed of chemicals with different MIE can exhibit mixture effects too, probably acting on the same biological pathway and contributing to the same adverse outcome (EFSA, 2013). This is in recognition of emerging evidence that biological effects can be similar, although the molecular details of toxicological mechanisms may profoundly differ in many respects (Kortenkamp, 2007). Considering the previously reported data, this could be the case of embryonic co-exposure to fluconazole (FLUCO) and ethanol (Eth). Both, in fact, lead to the same adverse outcome (AO), craniofacial malformations, both after in utero and in vitro exposure. The two molecules are able to induce cranio-facial defects (in embryos visible as cranio-facial abnormalities), probably acting on the same Adverse Outcome Pathway (AOP) altering, with different MIEs, the biological event cascade regulated by the morphogen retinoic acid (RA).
The specific aim of this PhD project was to investigate this hypothesis through the development of an in silico model, useful to simulate and predict the effects on embryo development after co-exposure to substances with independent MoAs but acting on the same biological pathway and potentially contributing to the same adverse outcome (cranio-facial malformations). The in silico model was based on experimental data and validated by in vitro experiments. For this purpose, the project was divided into three parts.
In the first part, we evaluated the effects of the molecules on post-implantation rat embryos cultures, using the in vitro technique WEC (Whole Embryo Culture). Embryos were cultured in presence of increasing concentration of RA (0.025-0.0375-0.05-0.125-0.25 µM), to increasing concentrations of Eth (17-42.5-85-127 mM), to increasing concentrations of FLUCO (62.5-125-250-500 µM). Specific and concentration related abnormalities at the level of the branchial arches (reductions or fusions) were observed after exposure to single Eth or FLUCO and were comparable to those elicited by RA. These results suggest a common AO for Eth, FLUCO and RA. Embryos were then co-exposed to binary mixtures of FLUCO and Eth. To better characterize the contribution of each component to the observed effects, the “fixed + moving” approach was applied: embryos were exposed to the no effect concentration (NOAEL) of one chemical (“fixed”) and increasing concentrations of the other chemical (“moving”). A significant enhancement of teratogenic effects was observed after co-exposure to FLUCO and Eth in comparison to the single exposure. The mixture between the two NOAELs was effective too, inducing almost 40% of branchial arch abnormalities. These data suggest the presence of a cumulative effect in mixture, probably due to the capability of both molecules to perturb RA endogenous concentrations in specific tissues (the precursors of cranio-facial skeletal tissues, originated in the embryonic hindbrain). This theory could be explained considering the ability of Eth to induce alcohol-dehydrogenases (including ADH7, the embryonic enzyme involved in RA synthesis) and the inhibitory effects of FLUCO on cytochromes p450 (including CYP26, involved in embryonic RA degradation).
In the second part of the project, we evaluated these hypothetical mechanisms inducing the Eth-FLUCO mixture effects through the development of an in silico tool, able to simulate both the formation of the physiological RA gradient in the rat embryo hindbrain and its perturbation after exposure to FLUCO, Eth and to their binary mixtures. The obtained system biology model, developed using an integrated approach combining mathematical modelling, molecular docking and in vitro experiments, seems to be reasonably predictive for the mixture’s effects, confirming the accuracy of the hypothesized pathogenic pathway. Experimental data and model predictions, in fact, showed a promising agreement. The model, in spite of its limitations, could have many potential mechanistic or predictive applications for the study of risk assessment. However, since the model is based on experimental data obtained in mammals, the last part of the project was aimed to evaluate alternative animal models.
In the third part of the project, the evaluation of the effects after co-exposure to FLUCO and Eth were performed using the ascidian Ciona intestinalis embryo model as a new alternative teratological screening test (AET, Ascidian Embryo Teratogenicity assay). An ascidian species was selected because Ascidiacea represent the sister group of Vertebrates. For this purpose, C. intestinalis embryos were exposed to Eth alone (1.7-8.5-17-42.5-85 mM) to FLUCO alone (7.8-15.75-31.5-250 µM), or co-exposed to binary mixtures of FLUCO and Eth until the larval stage, applying the fix + moving protocol. Specific and concentration related abnormalities at the level of the anterior structures were elicited by Eth or FLUCO, and were comparable to those described in literature after RA exposure. A significant enhancement of the general teratogenicity was observed after co-exposure to FLUCO and Eth in comparison to the single exposure, suggesting the presence of a mixture effect induced by FLUCO and Eth also in this model. These results, similar to those observed in the WEC model, encourage the use of AET as a complementary alternative method for embryotoxicity studies on mixtures. The possibility to translate data obtained in this model in our in silico model is still to evaluate.
In conclusion, our data suggest that: 1. the integrated use of data from in vitro and in silico approaches used in this study support the hypothesis that embryonic exposure to FLUCO and Eth can lead to the same AO (craniofacial abnormalities) acting with different MIEs but both converging on the same AOP by altering the RA production (Eth) and the RA catabolism (FLUCO); 2. the hypothesis that substances with different MoAs but acting on the same pathway could produce an additive effect also at concentrations considered not effective is supported; 3. the obtained results highlight the potential additive effect that could occur after exposure to azoles and ethanol, suggesting a precautionary position in alcohol consumption during azoles exposure in pregnancy. The overall view of the obtained results support the need of a cumulative risk assessment not only for chemicals grouped on the base of similarities in chemical structure or derived from mechanistic considerations but also for chemicals differently acting on the same biological pathway.
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Abou, Ammar Ghada [Verfasser], Holger B. [Akademischer Betreuer] Deising, and Petr [Akademischer Betreuer] Karlovsky. "Deletion mutagenesis of two ABC transporter genes in Fusarium graminearum and characterisation of their roles in azole tolerance and virulence / Ghada Abou Ammar ; Holger B. Deising, Petr Karlovsky." Halle, 2016. http://d-nb.info/1126503436/34.
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Amoedo, Machi Hugo [Verfasser], Gerhard [Akademischer Betreuer] Braus, Gerhard [Gutachter] Braus, Stefanie [Gutachter] Pöggeler, and Ralph [Gutachter] Kehlenbach. "The Aspergillus fumigatus Vap-Vip methyltransferase pathway modulates stress response, secondary metabolism and azole resistance / Hugo Amoedo Machi ; Gutachter: Gerhard Braus, Stefanie Pöggeler, Ralph Kehlenbach ; Betreuer: Gerhard Braus." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2019. http://d-nb.info/1190353644/34.
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De, oliveira Julie. "Utilisation de poissons zèbres génétiquement modifiés pour l'étude des mécanismes et des effets des perturbateurs endocriniens." Thesis, Paris, Institut agronomique, vétérinaire et forestier de France, 2020. http://www.theses.fr/2020IAVF0018.
Full textAbstract:
Les perturbateurs endocriniens (PE), présents dans les milieux aquatiques, constituent un risque pour les organismes aquatiques. Il parait donc nécessaire de développer et de mettre en œuvre des tests permettant d’évaluer les effets PE des substances. Dans ce contexte, les objectifs de cette thèse étaient d’étudier les effets et les mécanismes d’action de PE d’intérêt environnemental tant d’un point de vue moléculaire (stéroïdogenèse, vitellogenèse) que physiologique (fonction de reproduction). Pour cela, des lignées de poissons zèbres transgéniques (cyp11c1-eGFP, cyp11c1-eGFP-casper, cyp19a1a-eGFP, cyp19a1a-eGFP-casper) exprimant une protéine fluorescente sous le contrôle de promoteurs de gènes cibles des PE (gènes de la stéroidogenèse) ont été utilisés.Ce travail a permis de montrer qu’il n’y avait pas de différence entre les lignées transgéniques et la lignée sauvage (AB) que ce soit en termes de comportement (socialité, anxiété) ou de reproduction. Les différentes expositions à des fongicides azolés (clotrimazole, prochloraze, imazalil) ont mis en évidence l’absence de biais lié à l’insertion des transgènes, nos modèles transgéniques répondant aux substances de manière similaire aux poissons zèbres sauvages. Enfin, les différentes expositions ont permis d’évaluer les effets de fongicides azolés ainsi que de progestatifs de synthèse (norethindrone) sur la reproduction et l’expression de l’aromatase gonadique chez le poisson.Dans l’ensemble, ce travail de thèse a permis (i) d’évaluer en partie la sensibilité de chaque modèle transgénique par rapport aux lignées sauvages, (ii) de déterminer les avantages et les limites de chaque modèle, afin d’en proposer une utilisation fiable et pertinente pour l’étude des PE ; (iii) d’apporter des connaissances sur les effets PE de fongicides azolés et de progestatifs, notamment sur la reproduction des poissons zèbresEndocrine disrupters (EDs) are widespread aquatic environment contaminants that are at risk for aquatic organisms. In this regards, development and implementation of tests to identify EDs and quantify their effects is still a challenge. In this context, the objectives of this thesis were to study the effects and mechanisms of action of EDs of environmental interest both at the molecular (steroidogenesis, vitellogenesis) and physiological (reproductive function) levels. For that, transgenic zebrafish lines (cyp11c1-eGFP, cyp11c1-eGFP-casper, cyp19a1a-eGFP, cyp19a1a-eGFP-casper) expressing a fluorescent protein under the control of promoters of genes known to be targets of Eds (steroidogenic genes) were used.The present work showed that there exist no behavioral (sociality, anxiety) or reproductive differences between our transgenic lines and the wild type AB zebrafish. Exposures to azole fungicides (clotrimazole, prochloraz, imazalil) highlighted the absence of bias induced by the transgene insertions, our transgenic lines responding to substances like the wild-type zebrafish. Finally, the different exposures allowed us to evaluate the effects of azole fungicides and synthetic progestins (norethindrone) on reproduction and gonadal aromatase expression in fish.Overall, this thesis allowed (i) to evaluate the sensitivity of each transgenic model compared to wild-type zebrafish, (ii) to determine the strengths and weaknesses of each model to propose a reliable and relevant use for the study of EDs; (iii) to provide knowledge on the endocrine disrupting effects of azole fungicides and progestins, especially on zebrafish reproduction
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Marianetti, Giulia. "Synthesis, optical characterization and computational study of novel organic fluorophores." Doctoral thesis, Scuola Normale Superiore, 2017. http://hdl.handle.net/11384/85811.
Full textAbstract:
Over the last three decades lot of interest has been devoted to light harvesting technologies. Recent findings on global warming and energy nonrenewable resources push us to alternative means of storing energy. Sunlight stands indeed as an ideal asset to take advantage of. In this insight
Luminescent Solar Concentrators (LSCs) represent a way to decrease the cost of solar photovoltaics.
LSC devices usually consist in a thin slab of transparent material (glass or polymer) doped with a
fluorescent dye. Upon solar irradiation, a fraction of the emitted light, through means of internal
reflection, is collected at the edges of the device where photovoltaic cells are located. Compared to
traditional concentrators, which make use of mirrors and lenses, these devices show numerous
advantages, such as theoretical higher concentration factors, the ability to work with both diffuse and
incident light and no need for tracking devices or cooling apparatuses. Organic fluorescent dyes
bearing π-conjugated electron-donor and -acceptor moieties exhibit intramolecular charge-transfer
(ICT) properties, and can therefore show the optical properties required by LSCs such as high
quantum yield and high Stokes shift. On account of this, the present dissertation will discuss the
synthesis, UV-Vis characterization and computational study of a set of novel unsymmetrical and
symmetrical push-pull azole-based dyes. These compounds are characterized by a 1,3-azole 2,5
substituted with two aromatic moieties bearing electron withdrawing (EWG) or electron donating
(EDG) groups. Remarkably, the introduction of an heteroaromatic ring usually improves the thermal
and chemical stability and the overall polarizability of the fluorophore.
The studied compounds were prepared through a robust synthetic pathway involving a palladium
and copper-promoted direct C-H arylation reaction as key step. We took into account the effect of
the peripheral electron poor funtionality as well as the nature of the central heteroaromatic core. In
order to rationalize the experimental results we carried out TD-DFT studies, that allowed us to
proper understand the charge tranfer occuring during the electronic transition. After selecting the
best fluorophores for our aim, we investigated its efficiency in an LSC prototypes.
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Holloway, Mary Jolene Patricia. "Biochemical and Pharmacological Characterization of Cytochrome b5 Reductase as a Potential Novel Therapeutic Target in Candida albicans." Scholar Commons, 2011. http://scholarcommons.usf.edu/etd/3730.
Full textAbstract:
The opportunistic fungus Candida albicans is a commensal member of the human microflora and is the most common causative agent of fungal-related disease with particular significance in immunocompromised individuals. Emerging drug resistance is a major problem in Candida, contributed by enzymes involved in the detoxification of xenobiotics and pharmacological agents. One such enzyme, cytochrome b5 reductase (cb5r), has a high pharmacological significance owing to its role in fatty acid elongation, ergosterol (or cholesterol in mammals) biosynthesis, and cytochrome P450-mediated detoxification of xenobiotics.
We have compared the kinetic, biochemical, and pharmacological characteristics of C. albicans cb5r isoforms, Cbr1 and Mcr1, as compared to the mammalian control, rat cb5r. We have observed two key structural differences between the fungal and mammalian proteins that may account for decreased thermal stability and inhibitor specificity of C. albicans Cbr1. Substrate binding affinity and catalytic efficiencies, as well as investigation in the flavin-binding environment, were comparable between the fungal and rat enzymes. In S. cerevisiae, CBR1 and MCR1 knockout strains have been challenged with environmental stressors and subsequently shown to have a role in azole and amphotericin B resistance. Our results of potential protein interactions of C. albicans Cbr1 describe proteins involved in the weak acid stress response, implying a novel role of the protein in pathogenicity. Conclusively, this report describes potential inhibitors of the fungal protein, as well as elaborating upon its important role in ergosterol biosynthesis and possible mechanisms of CYP450-mediated drug detoxification.
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Bart-Delabesse, Emmanuelle. "Septicémies candidosiques dans un centre de brûlés : typage moléculaire et sensibilité aux antifongiques azolés des souches de "Candida albicans" et de "Candida parapsilosis"." Paris 5, 1994. http://www.theses.fr/1994PA05P187.
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Strasser, Christoph Erik. "New ligands for gold : bonding mode and structural complex characterisation." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/1466.
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Thesis (PhD (Chemistry and Polymer Science))--Stellenbosch University, 2008.Novel gold(I) trithiophosphite complexes were synthesised by utilising the ligands P(SR)3 (R = Me, Ph) and 1,2-bis(1,3,2-dithiaphospholan-2-ylthio)ethane (2L). Reaction with (tht)AuCl or (tht)AuC6F5 readily yielded the corresponding complexes (RS)3PAuX and 2L(AuX)2 (X = Cl, C6F5) as well as {Au[P(SMe)3]2}CF3SO3. Structural characterisation by X-ray diffraction revealed linear complexes in part associating by Au…Au and/or Au…S contacts, two polymorphs of one compound associating by either Au…S interactions or p-stacking was also obtained. (MeS)3PAuCl and (MeO)3PAuCl were found to be isostructural in the solid state. The complex chloro[tris(4-methylthiazol-2-yl)phosphane]gold, A, was used to probe the electronic influence tris(azol-2-yl)phosphanes exert upon gold(I) by substituting the chloride with various thiolates. In contrast to Ph3PAuCl, only NCS– and PhC(O)S– afforded stable compounds which could be attributed to a weaker donating capability of the tris- (azolyl)phosphane ligand class. The compounds A and chloro[tris(thiazol-2-yl)phosphane]- gold, B, were shown to crystallise in 4 new polymorphs and solvates bringing the total to an exceptional seven. Among the solid-state structures of A the rare instance of a polymorph and a thf solvate not exhibiting aurophilic interactions as opposed to the original structure were observed. Complex B was shown to crystallise in polymorphs where dimers are associated either by Au…Au or Au…Cl interactions but otherwise exhibit similar arrangements of the ligand, this set of polymorphs is unprecedented amongst gold complexes. An NMR experiment proved that tris(thiazolyl)phosphane complexes are subject to hydrolysis under alkaline conditions. A trimeric gold(I) heterometallacycle, obtained by reacting (tht)AuCl with 4,4-dimethyl-2-(2- thienyl)oxazoline deprotonated at C-5 of the thiophene ring, was structurally characterised. Intramolecular Au…S interactions were found to be present which precluded interaction of the gold atoms with other metal centres such as Me3CNCAuCl or AgNO3. A second solvate obtained additionally exhibits Au…Au interactions. The scope of uncommon bis-imine coordination to AuI was expanded by utilising 1,2-bis(1-imidazolylmethyl)-2,4,6-trimethylbenzene (2L) to synthesise the [Au2(μ-2L)2]2+ cation. The triflate salt forms the first porous crystal structure of gold and the co-crystallised solvent could be partially removed by evacuation at elevated temperatures. Utilising a ditopic phosphite ligand instead of the commonly used ditopic phosphane ligands, a new cationic species of the type [Au2(μ-2L)3]2+ was characterised in the solid state for the first time. Finally, employing 2-phenylthiazole and 1-(thiazol-2-yl)piperidine which can be deprotonated at C-5 of the thiazole ring, Fischer-type pentacarbonyltungsten carbeniate complexes were prepared and structurally characterised. Starting from these complexes, the analogous Fischertype methoxycarbene as well as carbyne complexes could be obtained by alkylation and formal oxide abstraction, respectively. The latter products readily formed dinuclear adducts with AuCl. A Fischer-type methoxycarbene could be transferred to AuI affording the first such gold(I) complex exhibiting Au…Au interactions in the solid state as well as a rare agostic Au…H interaction which was examined by low-temperature 1H NMR measurements. Transfer of the carbeniate ligand derived from 1-(thiazol-2-yl)piperidine to Ph3PAu+ afforded an aurated thiazole product (by an unprecedented loss of CO) which may be represented as a pseudoabnormal azolylidene complex owing to W(CO)5-coordination at a distant nitrogen. The carbeniate originating from 2-phenylthiazole, on the other hand, afforded, by rare W(CO)5- trapping and without CO-loss, a pseudo Fischer-type carbene complex. Carbene transfer to gold was complemented by the first transfers of rNHC ligands from chromium and tungsten to gold(I) affording a novel class of complexes, all of which were structurally characterised. This work bridges the unnatural divide created between Fischer and N-heterocyclic carbene complexes.
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Gigou-Cornet, Murielle. "Rôle des gènes RIM et VPS dans la signalisation du pH, la virulenceet la résistance aux antifongiques chez la levureCandida albicans." Phd thesis, INAPG (AgroParisTech), 2006. http://tel.archives-ouvertes.fr/tel-00143611.
Full textAbstract:
RésuméCandida albicans est le premier pathogène fongique de l'homme. Cette levure, habituellement
commensale, peut être à l'origine d'infections profondes mettant en jeu le pronostic
vital. L'incidence des candidoses profondes ne cesse d'augmenter parallèlement à
l'augmentation du nombre de patients à risque. La virulence de C. albicans s'explique par sa
capacité à coloniser puis envahir de nombreux tissus de l'organisme qui constituent autant de
microenvironnements différents. Les réponses adaptatives de la cellule aux modifications environnementales
sont déterminantes pour sa survie et conditionnent sa virulence. La voie
d'endocytose assure la dégradation ou le recyclage des protéines membranaires et joue un rôle
important dans la régulation des récepteurs. Elle est également impliquée dans l'activation de
la voie de signalisation du pH : la voie Rim.
Au début de ce travail, nous avons montré que la voie d'endocytose jouait un rôle majeur
dans la réponse au pH, la morphogenèse et la virulence de C. albicans, de façon à la fois
dépendante et indépendante de la voie Rim. Nous avons montré que les délétions de deux
gènes de la voie d'endocytose, VPS28 et VPS32, produisent non seulement les mêmes effets
que les délétions des gènes de la voie Rim, mais les aggravent.
Nous avons également mis en évidence le rôle de la voie Rim et des protéines Vps
dans la structure de la paroi et la résistance aux antifongiques azolés et aux échinocandines.
Là encore, la voie d'endocytose semble impliquée par son action spécifique dans la voie Rim
mais aussi par d'autres mécanismes indépendants de la voie Rim.
Enfin, nous avons caractérisé les mutants rim9 et rim21 et montré que les protéines
Rim9p et Rim21p sont toutes les deux indispensables à l'activation de la voie Rim chez C. albicans.
Ce résultat confirme que le mode d'activation de la voie Rim chez C. albicans est
proche de celui décrit chez S. cerevisiae et diffère sensiblement de celui d'Aspergillus nidulans
ou de Yarrowia lipolytica.
Nous avons montré que l'inhibition de la voie d'endocytose induit chez C. albicans
une réduction majeure de la virulence associée à une augmentation de la sensibilité aux antifongiques
azolés et aux échinocandines. En permettant la potentialisation de l'efficacité des
molécules existantes cette voie pourrait constituer une cible intéressante pour le développement
de nouveaux traitements antifongiques.
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Ohnmacht, Stephan A. "Direct arylations of azoles." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/11233.
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Navarro, Rodríguez Patricia. "Mecanismos de resistencia a azoles en especies de candida no-albicans." Doctoral thesis, Universitat Rovira i Virgili, 2019. http://hdl.handle.net/10803/667563.
Full textAbstract:
La candidiasis invasora és una infecció fúngica de gran importància clínica, pot ser causada per diverses espècies de Candida. Encara que l’espècie més comuna és Candida albicans, als últims anys hi ha hagut un augment de infeccions produïdes per altres especies com Candida glabrata, Candida parapsilosis, Candida tropicalis u Candida krusei. Totes elles són les responsables del 90% de les micosis invasores a nivell mundial. L’espectre de la candidiasis varia d’una candidemia mínimament simptomàtica fins a una sèpsia fulminant amb una alta mortalitat. El diagnòstic precoç d’aquesta malaltia es clau per l’elecció del tractament antifúngic adequat, els fàrmacs de primera línia emprats son les equinocandines i els azols. Però un dels principals problemes d’aquestes infeccions és el recent augment de aïllats resistents als antifúngics d’us clínic. A l’actualitat els azols són els més freqüentment emprats en el tractament de la candidiasis, degut a la seva baixa toxicitat i a la possibilitat de ser administrats per la via oral. Existeix una amplia documentació recent sobre la resistència que molts aïllats de diferents espècies de Candida presenten en front els azols. El objectiu principal d’aquesta tesi doctoral ha estat avaluar els mecanismes de resistència a voriconazol en tres espècies de Candida: C. glabrata, C. parapsilosis i C. tropicalis, per intentar esbrinar el seu fonament i per tant millorar el tractament d’aquestes infeccions fúngiques. Per això s’han portat a cap estudis moleculars sobre els mecanismes de resistència més importants, avaluant la relació dels gens candidats ERG11, CDR1, CDR2 i SNQ2 amb la disminució de la sensibilitat al voriconazol, de les mencionades especies.La candidiasis invasora es una infección micótica de gran importancia clínica que puede ser causada por varias especies de Candida. Aunque la especie más común es Candida albicans, en los últimos años ha habido un aumento de infecciones producidas por otras especies tales como Candida glabrata, Candida parapsilosis, Candida tropicalis y Candida krusei. Todas ellas son responsables del 90% de las micosis invasoras a nivel mundial. El espectro de la candidiasis varía desde una candidemia mínimamente sintomática hasta una sepsis fulminante con una alta mortalidad asociada. El diagnostico precoz de esta enfermedad es clave para la elección de un tratamiento antifúngico adecuado, los fármacos de primera línea utilizados son las equinocandinas y los azoles. Sin embargo, uno de los principales problemas de estas infecciones es el reciente aumento de aislados resistentes a los antifúngicos de uso clínico. En la actualidad los azoles son los más frecuentemente usados en el tratamiento de la candidiasis, debido a su baja toxicidad y a la posibilidad de ser administrados por la vía oral. Existe una amplia documentación reciente sobre la resistencia que muchos aislados de diferentes especies de Candida presentan frente a los azoles. El objetivo principal de esta tesis doctoral ha sido evaluar los mecanismos de resistencia a voriconazol en tres especies de Candida: C. glabrata, C. parapsilosis y C. tropicalis para intentar arrojar luz sobre este asunto y mejorar el tratamiento terapéutico de estas infecciones fúngicas. Para ello se han llevado a cabo estudios moleculares de los mecanismos de resistencia principalmente descritos, evaluando la relación de los genes candidatos ERG11, CDR1, CDR2 y SNQ2 con la disminución de la sensibilidad a voriconazol de estas especies.
Invasive candidiasis is a fungal infection with high clinical importance that can be caused by several species of Candida. Although the most common species is Candida albicans, in recent years infections caused by other species such as Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei have been increased. All of them are responsible for 90% of the invasive mycosis worldwide. The spectrum of candidiasis ranges from minimally symptomatic candidemia to fulminant sepsis with high mortality associated. The early diagnosis of this disease is a key to choice an appropriate antifungal treatment; the first-line drugs used are the echinocandins and azoles. However, one of the main problems of these infections is the recent increase of resistant isolates to antifungal for clinical use. At present, azoles are the most frequently used for candidiasis treatmen, due to its low toxicity and the possibility of being administered orally. There is extensive recent documentation on the resistance that many isolates of different species of Candida have against azoles. The main objective of this doctoral thesis was to evaluate the mechanisms of resistance to voriconazole in three species of Candida: C. glabrata, C. parapsilosis and C. tropicalis to try to throw light on this issue and improve the therapeutic treatment of these fungal infections. To this end, molecular studies of the mainly described mechanisms of resistance have been carried out, evaluating the relation of the candidate genes ERG11, CDR1, CDR2 and SNQ2 with the decrease in the voriconazole susceptibiliy of these species.