Foram estudados 83 pacientes com esofagite erosiva graus I e II, pela classificação de Savary-Miller modificada, divididos em 3 grupos. Um sem Helicobacter pylori, dois outros com Helicobacter pylori, com e sem o gene cagA. Avaliou-se a participação da bactéria e de seu gene cagA, associados à estudo histopatológico de antro e corpo e à gastrinemia basal, na cicatrização da mucosa do esôfago após tratamento com pantoprazol 40 mg ao dia por 6 semanas. Verificou-se que a presença do Helicobacter pylori, independentemente da presença do gene cagA, facilita a cicatrização esofágica. Indivíduos com gastrinemias maiores também tendem a cicatrizar melhor. Não houve relação do resultado do estudo histopatológico com a resposta terapêutica / Eighty three patients with grade I-II of the modified Savary-Miller classification have been studied. They were divided in three groups. One without Helicobacter pylori infection, two with the bacterium, one with and other without the cagA gene. We verified the influence of cagA status, histopathology of antrum and body of the stomach and gastrinemia in the esophageal healing rates after treatment with pantoprazole 40 mg once a day for six weeks. Helicobacter pylori presence but not cagA status and gastrinemia led to better healing rates. Histopathology of the gastric mucosa did not influence the response

Indiana University-Purdue University Indianapolis (IUPUI) / The DNA minor groove continues to be an important biological target in the development of anticancer, antiviral, and antimicrobial compounds. Among agents that target the minor groove, studies of well-established benzimidazole-based DNA binders such as Hoechst 33258 have made it clear that the benzimidazole-amidine portion of these molecules promotes an efficient, site-selective DNA association. Building on the beneficial attributes of existing benzimidazole-based DNA binding agents, a series of benzimidazole-amino acid conjugates was synthesized to investigate their DNA recognition and binding properties. In this series of compounds, the benzimidazole-amidine moiety was utilized as a core DNA “anchoring” element accompanied by different amino acids to provide structural diversity that may influence DNA binding affinity and site-selectivity. Single amino acid conjugates of benzimidazole-amidines were synthesized, as well as a series of conjugates containing 20 dipeptides with the general structure Xaa-Gly. These conjugates were synthesized through a solid-phase synthetic route building from a resin-bound amino acid (or dipeptide). The synthetic steps involved: (1) the coupling of 4-formylbenzoic acid to the resin-bound amino acid (via diisopropylcarbodiimide and hydroxybenzotriazole); followed by (2) introduction of a 3,4-diaminobenzamidoxime in the presence of 1,4-benzoquinone to construct the benzimidazole ring; and, finally, (3) reduction of the resin-bound amidoxime functionality to an amidine via treatment with 1M SnCl2•2H2O in DMF before cleavage of final product from the resin. The synthetic route developed and employed was simple and straightforward except for the final reduction that proved to be very arduous. All target compounds were obtained in good yield (based upon weight), averaging 73% mono-amino acid and 78% di-amino acid final compound upon cleavage from resin. Ultimately, the DNA binding activities of the amino acid-benzimidazole-amidine conjugates were analyzed using a fluorescent intercalator displacement (FID) assay and calf thymus DNA as a substrate. The relative DNA binding affinities of both the mono- and di-amino acid-benzimidazole-amidine conjugates were generally weaker than that of netropsin and distamycin with the dipeptide conjugates showing stronger binding affinities than the mono-amino acid conjugates. The dipeptide conjugates containing amino acids with positively charged side chains, Lys-Gly-BI-(+) and Arg-Gly-BI-(+), showed the strongest DNA binding affinities amongst all our synthesized conjugates.

No / The 70 eV electron impact mass spectra of a wide range of 2-substituted benzazoles are reported and discussed. Particular attention is paid to the mechanistic significance and analytical utility of [M–H]+ and [M–X]+ signals in the spectra of benzazoles in which the 2-substituent contains a terminal aryl group with one or more substituents, X. Loss of H or X occurs preferentially from an ortho-position from ionized 2-benzylbenzimidazoles, 2-phenethylbenzimidazoles, 2-styrylbenzimidazoles, 2-styrylbenzoxazoles and 2-styrylbenzothiazoles. In the three styrylbenzazole series, the [M–H]+ and/or [M–X]+ signals dominate the spectra. This unusually facile loss of H or X may be attributed to a proximity effect, in which cyclization of the ionized molecule is followed by elimination of an ortho-substituent to give an exceptionally stable polycyclic ion. Formation of a new five- or six-membered ring by the proximity effect occurs rapidly; cyclization to a seven-membered ring takes place rather less readily; but formation of a ring with only four atoms or more than seven atoms is not observed to a significant extent. The proximity effect competes effectively with loss of a methyl radical by simple cleavage of an ethyl, isopropyl and even a t-butyl group in the pendant aromatic ring of ionized 2-(4-alkylstyryl) benzazoles.

Les métalloenzymes d’origine naturelle constituent une riche source d’inspiration pour la conception de catalyseurs synthétiques en raison de leur capacité à réaliser des réactions d’oxydation sélective dans des conditions douces. Parmi ces métalloenzymes, les amine-oxydases à cuivre (CuAOs) permettent l’oxydation sélective des amines primaires grâce à la coopération d’un catalyseur organique quinonique (topaquinone) et d’un ion cuivrique. Récemment, un regain d’intérêt s’est manifesté pour le développement de catalyseurs biomimétiques permettant l’oxydation des amines en imines à l’air ambiant, en raison de l’importance des imines comme intermédiaires de synthèse en chimie fine et en pharmacologie. Au laboratoire, un système co-catalytique mimant l’activité des CuAOs a été décrit pour l’oxydation, à l’air ambiant, des amines primaires en imines, permettant une forte économie d’atomes. Le procédé catalytique comprend deux couples redox comparables à ceux des CuAOs : le catalyseur organique o-iminoquinonique 1ox, généré in situ à partir de l’o-aminophénol correspondant 1red, est le véritable catalyseur de l’oxydation de l’amine substrat, tandis que le sel de cuivre (II) sert de médiateur redox. Il est intéressant de noter que de faibles quantités de sel de cuivre (II) biocompatible et de catalyseur organique 1ox suffisent à activer la liaison C-H située en α de la fonction NH2 des amines primaires aliphatiques, qui sont converties, à l’air ambiant, en imines issues du couplage hétérolytique, à l’issue d’un processus de transamination qui conduit à l’imine résultant du couplage homolytique, suivi d’une réaction de transimination. Les conditions douces utilisées sont particulièrement intéressantes d’un point de vue synthétique, notamment pour engager les alkylimines instables in situ dans des réactions subséquentes. Aussi, avons-nous envisagé d’utiliser ce système co-catalytique bioinspiré dans la synthèse one-pot d’hétérocycles d’intérêt pharmacologique. Dans la première partie de la thèse, nous avions l’intention d’utiliser le système co-catalytique Cu(II)/1ox dans la synthèse de nouveaux dérivés de la 1,4-benzoxazine. Dans le cas particulier des amines primaires de type R1R2CHCH2NH2, le processus catalytique se trouvait bloqué après un certain nombre de cycles catalytiques en raison de l’engagement du catalyseur 1ox dans une réaction de Diels-Alder à demande électronique inverse avec la forme énamine tautomère de l’imine éliminée au cours du processus catalytique, conduisant ainsi aux dérivés de la 1,4-benzoxazine. Toutefois, l’utilisation de ce procédé s’avéra un échec, les énamines générées étant trop instables à l’air ambiant pour permettre l’isolement des dérivés de la 1,4-benzoxazine avec des rendements acceptables. Nous avons ainsi été amenés à développer une réaction alternative en tandem : les dérivés o-aminophénols sont oxydés dans le méthanol sous atmosphère d’azote, à l’aide d’une quantité stoechiométrique de dioxyde de manganèse activé, en o-iminoquinones. Ces hétérodiènes sont ensuite piégés in situ par différentes énamines diénophiles pour conduire aux dérivés de la 1,4-benzoxazine attendus, dans des conditions douces. La possibilité d’introduire des éléments de diversité dans chacun des partenaires de la cycloaddition permet de préparer des dérivés de la 1,4-benzoxazine hautement substitués. Parmi ces composés, un dérivé présentant deux groupements phényle en position 3 s’est avéré présenter une activité neuroprotectrice notable chez la souris nouveau-né, faisant de lui un candidat potentiel pour le traitement et la prévention de la paralysie cérébrale du nouveau-né. Dans la seconde partie de la thèse, le système co-catalytique Cu(II)/1ox est utilisé dans une réaction de couplage oxydatif d’amines primaires, activées ou non, avec des o-aminoanilines conduisant ainsi à des dérivés du benzimidazole d’intérêt biologique au travers d’un procédé multi-étapes. (...) / Naturally occurring metalloenzymes constitute a rich source of inspiration for the design of synthetic catalysts because of their ability to perform controlled aerobic oxidations under very mild conditions. Among metalloenzymes, copper amine oxidases (CuAOs) promote selective aerobic oxidation of primary amines through the cooperation of a quinone-based cofactor (topaquinone) and a copper ion. Recently, there has been a boost in the development of biomimetic catalysts for the aerobic oxidation of amines to imines owing to the importance of imines as pivotal intermediates in the synthesis of fine chemicals and pharmaceuticals. In our laboratory, a CuAOs-like homogeneous co-catalytic system has been described for the atom-economical oxidation of primary amines to imines, under ambient air. The catalytic process combines two redox couples in a way reminiscent of CuAOs: the o-iminoquinone organocatalyst 1ox, generated in situ from the corresponding o-aminophenol 1red, is the substrate-selective catalyst, whereas the copper (II) salt serves as an electron transfer mediator. Interestingly, low loadings of biocompatible CuII and organocatalyst 1ox are sufficient to activate the α-C-H bond of primary aliphatic amines, which are converted, under ambient air, into cross-coupled imines through a transamination process that leads to the homocoupled imine intermediate, followed by dynamic transimination. The mild reaction conditions are highly favorable from a synthetic viewpoint, in particular for trapping the unstable alkylimines in situ for further reactions. So, we have envisioned the use of this bioinspired co-catalytic system in the one-pot synthesis of heterocycles of pharmacological interest. In the first part of the thesis, we envisioned that the Cu(II)/1ox cooperative system might be utilized to synthesize novel 1,4-benzoxazine derivatives. In the specific case of R1R2CHCH2NH2 amines, the catalytic process should stop after a few turnovers, because the catalyst 1ox should be trapped through inverse-electron-demand Diels-Alder (IEDDA) reaction with the simultaneously in situ generated tautomeric enamine form of the alkylimine extruded during the catalytic process, leading to 1,4-benzoxazine derivatives. Unfortunately, this protocol failed to produce the expected cycloadducts in acceptable yields as enamines rapidly decomposed under ambient air. For this reason, we have developed a tandem oxidation-inverse electron demand Diels-Alder reaction as an alternative: a stoichiometric amount of activated MnO2, in deaerated methanol, was then sufficient to convert various o-aminophenol derivatives into o-iminoquinone heterodienes which were trapped in situ by different enamine dienophiles leading to the expected 1,4-benzoxazine derivatives under mild conditions. The possibility of introducing variations in both cycloaddition partners led to highly substituted 1,4-benzoxazine cycloadducts with up to five elements of diversity. Among these compounds, a 3,3-diphenyl-substituted-1,4-benzoxazine derivative was identified as an effective neuroprotective agent in newborn mice, suggesting that it could be a potential candidate for the treatment and prevention of cerebral palsy. In the second part of the thesis, the Cu(II)/1ox cooperative system has been successfully used for the catalytic oxidative coupling of a diverse range of activated and non-activated primary amines with o-amino-anilines under ambient air leading to benzimidazoles of biological interest through multistep oxidation and nucleophilic addition reactions. Through the variation of both solvent and coupling partners, MeOH proved to be the best solvent for this transformation because it provided the ideal balance of 1ox solvation and reaction rate, except when reactive N-alkyl o-aminoanilines were used as in situ imine traps, due to the concomitant formation of a benzimidazole byproduct originated from MeOH itself. (...)

Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes. / This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes.

Ce manuscrit de thèse concerne le développement d'une stratégie de synthèse multi-étapes de nouveaux composés comportant plusieurs plateformes hétérocycliques (rhodanine, benzimidazole, pyrazole et imidazole) à visée thérapeutique multiple contre la malaria, la leishmaniose, le cancer et les maladies neurodégénératives. Les pharmacomodulations de ces composés ont été élaborées sur la base du modèle de la pentamidine 35 comportant 2 motifs benzamidines (parties « Ouest » et « Est »). En effet, la substitution de sa partie « Ouest » par une plateforme rhodanine ou benzimidazole et de sa partie « Est » par un système aromatique plan ou système azole (pyrazole, imidazole) a permis d’accéder respectivement aux 5-arylidènes rhodanines (50, 58), aux dérivés ''aza'' (99,100) et aux dérivés ''aza azoles'' 174 qui sont des analogues de la pentamidine. Les rendements de ces composés sont respectivement compris entre 26 et 98%, 10 et 93% et 10 et 97%. L’ensemble des composés synthétisés dans les chapitres II, III et IV de ces travaux ont été l'objet d'évaluations pour leur activité antiproliférative sur les lignées cellulaires et pour leur activité inhibitrice sur les protéines kinases. / This thesis manuscript is focused on the development of multi-steps synthesis strategy of new compounds bearing several heterocyclic platforms (rhodanine, benzimidazole, pyrazole and imidazole) for multiple therapeutic use to fight malaria, leishmaniasis, cancer et neurodegenarative diseases. The pharmacomodulations of these compounds were developped from the design of pentamidine 35 which containins 2 fragments benzamidine (parts ''West'' and ''East''). Indeed, the substitution of its part ''West'' by a platform rhodanine or benzimidazole and its part ''East'' by an "azole" aromatic ring system (pyrazole, imidazole) lead respectively to 5-arylidene rhodanines (50, 58), to derivatives ''aza'' (99,100) and to derivatives ''aza azoles'' 174 which are pentamidine analogs. The chemical yields of these compounds are ranging respectively from 26 to 98%, 10 to 93% and 10 to 97%. All the compounds synthesized in the chapters II, III and IV of this research work were evaluated for their antiproliferative activity on tumoral cell lines and for their inhibitory activity on protein kinases.

Ces travaux de thèse traitent de la synthèse et de la fonctionnalisation d’hétérocycles azotés catalysées par les métaux de transition. La première partie de ce projet a été consacrée à la mise en place d’une méthode simple et efficace pour la N-cyclopropylation de différents composés azotés. A partir de l’acide cyclopropylboronique, en présence de sels de cuivre et dans des conditions de couplage oxydant, une grande variété de composés azotés ont pu être N-cyclopropylés. Cette méthode permet une nouvelle voie d’accès aux substrats N-cyclopropylés.La deuxième partie de ces travaux de thèse porte sur l’étude de la synthèse de benzimidazole. Ces hétérocycles azotés ont pu être obtenus à partir d’amidines grâce à une séquence réactionnelle faisant intervenir une réaction de N-arylation suivi d’une cyclisation via la fonctionnalisation d’une liaison C-H.La troisième partie de ce manuscrit se focalise sur la synthèse de pyrroles. Cette famille de composés est réputée pour son abondance dans les molécules biologiquement actives. Nous avons développé une réaction séquentielle monotope, permettant la synthèse de N-H pyrroles poly-fonctionnalisés via la formation d’un énaminone, catalysée par de l’indium (III), suivi d’une étape d’hétéroannulation catalysée par du palladium.Enfin, la dernière partie de ce projet scientifique décrit notre approche vers la synthèse totale d’un alcaloïde : la (-)-norsuavéoline. L’originalité de notre approche est basée sur la synthèse, dans un premier temps, du noyau pyridinique de la molécule à partir de l’acide L-(-)-glutamique, pour finir par la formation tardive du noyau indolique. Jusqu’à maintenant, nous avons développé et optimisé la synthèse de la pyridine. Des études sont toujours en cours au laboratoire afin de former la partie indolique et de terminer cette synthèse. / These scientific project deals with synthesis and functionalization of nitrogen heterocycles catalyzed by transition metals. The first part of this project was devoted to the development of a simple and efficient reaction for the N-cyclopropylation of various nitrogen compounds. From cyclopropylboronic acid under copper oxidative coupling conditions, a wide variety of nitrogen compounds have been N-cyclopropylated. This method allows a new access to N-cyclopropylated substrates.The second part of this work deals with benzimidazoles synthesis. These nitrogen heterocycles have been obtained from amidines through a sequence involving a N-arylation reaction followed by cyclization via a C-H bond functionalization.The third part of this manuscript focuses on pyrroles synthesis. Pyrroles are known for their abundance in biologically active molecules. We have developed a new sequential one-pot procedure for poly-functionalized N-H pyrroles synthesis. Through a enaminone formation catalyzed by indium (III), followed by a palladium catalyzed heteroannulation, various N-H pyrroles have been synthesizedThe final part of this scientific project describes our approach to total synthesis of an alkaloid: the (-)-norsuavéoline. The specificity of our approach was based on the formation of pyridine ring in the beginning of the synthesis and a late formation of indole ring. To date, we have developed and optimized the pyridine synthesis from L-(-)-glutamic acid. Studies are ongoing in the laboratory to obtain the indole part and complete the synthesis of this natural product.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-11T20:15:29Z No. of bitstreams: 1 viniciuszamprognomota.pdf: 2945652 bytes, checksum: 2543aba1c0b97eaf6ce52fe22b1d8f33 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-07-13T16:38:27Z (GMT) No. of bitstreams: 1 viniciuszamprognomota.pdf: 2945652 bytes, checksum: 2543aba1c0b97eaf6ce52fe22b1d8f33 (MD5) / Made available in DSpace on 2016-07-13T16:38:27Z (GMT). No. of bitstreams: 1 viniciuszamprognomota.pdf: 2945652 bytes, checksum: 2543aba1c0b97eaf6ce52fe22b1d8f33 (MD5) Previous issue date: 2012-02-28 / Certos íons metálicos bem como seus complexos estão presentes em sistemas biológicos exercendo importantes funções biológicas. No entanto, a utilização dos íons metálicos e de seus compostos, no início, era de modo empírico. A investigação sistemática científica de complexos parece ter vindo somente após os estudos de Paul Ehrlich e Robert Koch. Bases de Schiff diimínicas, assim como seus derivados benzimidazóis, possuem atividades biológicas conhecidas. Alguns complexos contendo vanádio (IV ou V) e de ouro (I ou III) também possuem reconhecidos usos biológicos. Portanto, complexos envolvendo as Bases de Schiff diíminicas e benzimidazóis com íons metálicos de vanádio e de ouro é um importante tema de estudo dentro do campo da Química Bioinorgânica. Dentro deste contexto, este trabalho tratou da síntese e caracterização de bases de Schiff diimínicas e benzimidazóis obtidos a partir da condensação entre 1,2-fenilenodiamina e benzaldeído ou seus derivados. Este trabalho também relata a síntese, caracterização e estudo biológico de complexos envolvendo bases de Schiff diimínicas e benzimidazóis obtidos com os íons de vanádio (IV) e de ouro (I e III). Ao final, são relatados quatorze compostos, sendo seis ligantes e oito complexos. Sete destes compostos ainda não foram relatados na literatura. Os compostos, exceto IMOH e [AuIIMOMeCl], foram testados contra protozoários do gênero Leishmania na etapa promastigota, sendo as espécies L. amazonesis, L. braziliensis, L. chagasi e L major. Os resultados mais expressivos foram encontrados para os compostos envolvendo o íon AuIII. Os complexos de AuIII também foram testados contra a fase amastigota do parasita contra as espécies L. amazonesis, L. braziliensis e L major. / The metal ions and their complexes are present in biological systems exersing important biological functions. However, the use of metal ions and their compounds, it was empirically. Systematic investigation of metals complexes seems to have come only after the studies of Paul Ehrlich and RobertKoch. Diiminics Schiff bases, as well as benzimidazole derivatives, have known biological activities. Some complexes containing vanadium (IV or V) and gold (I or III) also have recognized biological uses. Therefore, complexes involving Schiff Bases diíminicas and benzimidazole metal ions vanadium and gold is a major field of study within the field of Bioinorganic Chemistry. Within this context, this paper deals with the synthesis and characterization of Schiff bases and diimínicas benzimidazole obtained from the condensation between benzaldehyde and 1,2-phenylenediamine or its derivatives. This paper also reports the synthesis, characterization and biological study of complexes involving Schiff bases and diimínicas benzimidazole obtained with ions of vanadium (IV) and gold (I and III). In the end, fourteen compounds are reported, six and eight ligand complexes. Seven of these compounds have not been reported in the literature. The compounds, except IMOH and [AuIIMOMeCl], were tested against the protozoa of the Leishmania promastigote stage, with the species L. amazonesis, L. braziliensis, L. chagasi and L major. The most significant results were found for compounds involving ion AuIII. The AuIII complexes were also tested against the amastigote stage of the parasite species against L. amazonesis, L. braziliensis and L major.

[ES] En este trabajo de tesis doctoral se ha llevado a cabo la síntesis de diferentes materiales de tipo metal-orgánico (MOFs) para su aplicación en procesos catalíticos heterogéneos en la obtención de productos químicos de un alto valor añadido. Al-ITQ-HB es un material híbrido en 2D que ha mostrado actividad para la síntesis quimioselectiva de benzimidazoles, muy utilizados en la industria farmacéutica, y para la reacción de cianosililación de compuestos carbonílicos. El material se mostró estable bajo las condiciones de reacción e incluso activo en disoluciones acuosas lo cual se puede explicar debido a su carácter hidrofóbico. MOFs de Zr y Hf como UiO-66 y MOF-808 son activos para la reacción de reducción de compuestos carbonílicos procedentes de la biomasa por transferencia de hidrógeno con isopropanol como agente reductor. Esta metodología permite sustituir metales nobles como el Pd y el Pt por otros más baratos como el Zr y el Hf y también utiliza alcoholes como agentes reductores y a la vez como disolvente, evitando la peligrosidad de trabajar con H2. Los materiales de Hf se mostraron más activos que los de zirconio para la transformación, siendo el Hf-MOF-808 el más activo. Hf-MOF-808 y UiO-66(Hf) son activos para la reacción de condensación aldólica entre aldehídos y acetona. Sin embargo, Hf-MOF-808 se mostró más estable y activo para la transformación frente a contaminantes comunes en las disoluciones del procesado de la biomasa como son el ácido acético y el agua. Además este proceso se puede aplicar a un número elevado de sustratos de partida, incluidas moléculas plataforma procedentes de la biomasa como el furfural, el 5-hidroximetilfurfural y el 5-metilfurfural. El material se pudo extraer del crudo de reacción y reutilizar hasta en 5 ocasiones consecutivas con pequeñas pérdidas de actividad que podrían ser recuperadas a través de una extracción Soxhlet. Hf-MOF-808 se pudo utilizar en reacciones en cascada. Debido a su actividad para la reacción de reducción por transferencia de hidrógeno y para la de condensación aldólica, Hf-MOF-808 se utilizó como catalizador para la síntesis de alcoholes alílicos a partir de aldehídos y acetona. Además se pudieron soportar partículas de Pd en el MOF. El material resultante, Pd@Hf-MOF-808, se utilizó como catalizador en la reacción de condensación de compuestos carbonílicos y acetona/hidrogenación selectiva del doble enlace para dar 4-aril-2-butanonas. La mezcla física de una zeolita con acidez de Brønsted como Al-beta y Hf-MOF-808 permite usarla en la síntesis en cuatro pasos de GVL a partir de furfural en un mismo reactor. Zr-MOF-808 se muestra activo y selectivo para la formación de arilcarbamatos a partir de aminas aromáticas y DMC. El DMC es un sustituto sostenible del fosgeno. Estos materiales pierden su cristalinidad bajo las condiciones de reacción. Con el objetivo de mejorar la estabilidad se estos materiales, Zr-MOF-808 se ancló a la sílice mesoporosa MCM-41. Zr-MOF-808@MCM-41 se mostró activo y selectivo para la formación de arildicarbamatos precursores de poliuretanos a partir de diaminas y DMC. Además el material se puedo reusar hasta en 6 ocasiones sin pérdidas apreciables de actividad. El empleo de SiO2 también es viable como soporte, siendo este mucho más barato que la MCM-41. / [CAT] En este treball de tesi doctoral s'ha dut a terme la síntesi de diversos materials de tipus metall-orgànic (MOFs) per a la seua aplicació en processos catalítics heterogenis en l'obtenció de productes químics d'un alt valor afegit. Al-ITQ-HB és un material híbrid en 2D que ha mostrat activitat per a la síntesi quimioselectiva de benzimidazoles, molt utilitzats en la indústria farmacèutica, i per a la reacció de cianosililació de compostos carbonílics. El material es va mostrar estable sota les condicions de reacció i inclús actiu en dissolucions aquoses la qual cosa es pot explicar a causa del seu caràcter hidrofòbic. MOFs de Zr i Hf com l'UiO-66 i el MOF-808 són actius per a la reacció de reducció per transferència d'hidrogen de compostos carbonílics procedents de la biomassa amb isopropanol com a agent reductor. Esta metodologia permet substituir metalls nobles com el Pd i el Pt per altres més barats com el Zr i el Hf i també utilitza alcohols com a agents reductors i al mateix temps com a dissolvent, evitant la perillositat de treballar amb H2. Els materials de Hf es van mostrar més actius que els de zirconi per a la transformació, sent el Hf-MOF-808 el més actiu. Hf-MOF-808 i UiO-66 (Hf) són actius per a la reacció de condensació aldòlica entre aldehids i acetona. No obstant això, Hf-MOF-808 es va mostrar més estable i actiu per a la transformació treballant amb contaminants comuns en les dissolucions del processat de la biomassa com són l'àcid acètic i l'aigua. A més este procés es va poder aplicar a un nombre elevat de substrats de partida, incloses molècules plataforma procedents de la biomassa com el furfural, el 5-hidroximetilfurfural i el 5-metilfurfural. El material es va poder extraure del cru de reacció i reutilitzar fins en 5 ocasions consecutives amb xicotetes pèrdues d'activitat que podrien ser recuperades a través d'una extracció Soxhlet. Hf-MOF-808 es va poder utilitzar en reaccions tàndem. A causa de la seua activitat per a la reacció de reducció per transferència d'hidrogen i per a la de condensació aldòlica, Hf-MOF-808 es va utilitzar com a catalitzador per a la síntesi d'alcohols alílics a partir d'aldehids i acetona. A més es van poder suportar partícules de Pd en el MOF. El material resultant, Pd@Hf-MOF-808, es va utilitzar com a catalitzador en la reacció de condensació de compostos carbonílics i acetona/hidrogenació selectiva del doble enllaç per a donar 4-aril-2-butanonas. La mescla física d'una zeolita amb acidesa de Brønsted com Al-beta i Hf-MOF-808 permet utilitzar-la en la síntesi en quatre passos de GVL a partir de furfural en un mateix reactor. Zr-MOF-808 es mostra actiu i selectiu per a la formació d'arilcarbamats a partir d'amines aromàtiques i DMC. El DMC és un substitut sostenible del fosgen. Estos materials perden la seua cristalinidat sota les condicions de reacció. Amb l'objectiu de millorar l'estabilitat d'estos materials, Zr-MOF-808 es va ancorar a la sílice mesoporosa MCM-41. Zr-MOF-808@MCM-41 es va mostrar actiu i selectiu per a la formació d'arildicarbamats, precursors de poliuretans, a partir de diamines i DMC. A més el material es pot reutilitzar fins en 6 ocasions sense pèrdues apreciables d'activitat. L'ocupació de SiO2 també és viable com a suport, sent este molt més barat que la MCM-41. / [EN] The synthesis of different metal-organic type materials (MOFs) such as Al-ITQ-HB, UiO-66, UiO-67 and MOF-808 has been carried out in this doctoral thesis. The final goal was its application in heterogeneous catalytic processes in the production of value-added chemicals. Al-ITQ-HB is a 2D hybrid material that has shown activity for the chemoselective synthesis of benzimidazoles, widely used in the pharmaceutical industry, and for the cyanosilylation reaction of carbonyl compounds. The material was stable under the reaction conditions and even active in aqueous solutions which could be explained by its hydrophobic pockets. Zr- and Hf-MOFs such as UiO-66 and MOF-808 are active for the catalytic transfer hydrogenation of biomass-based carbonyl compounds using isopropanol as a reducing agent. This methodology allows to substitute noble metals such as Pd and Pt for cheaper ones such as Zr and Hf and also uses alcohols as reducing agents and as a solvents, avoiding the danger of working with H2. Hf materials were more active than zirconium-counterparts in the transformation, with Hf-MOF-808 being the most active. Hf-MOF-808 and UiO-66(Hf) are active for the aldol condensation reaction between aldehydes and acetone. However, Hf-MOF-808 was more stable and active in the transformation with common contaminants in the biomass-derived solutions such as acetic acid and water. In addition, this process could be applied to a large number of starting materials, including platform molecules from biomass such as furfural, 5-hydroxymethylfurfural and 5-methylfurfural. The material could be extracted from the reaction mixture and reused up to 5 consecutive times with small losses of activity that could be recovered through a Soxhlet extraction. Hf-MOF-808 could be used in cascade reactions. Due to its activity for the catalytic transfer hydrogenation and for the aldol condensation reaction, Hf-MOF-808 was used as a catalyst for the synthesis of allylic alcohols from aldehydes and acetone. In addition, Pd particles could be supported in the MOF. The resulting material, Pd@Hf-MOF-808, was used as a catalyst in the condensation reaction of carbonyl compounds and acetone/selective hydrogenation of the double bond to give 4-aryl-2-butanones. On the other hand, the physical mixture of a zeolite with Brønsted acidity such as Al-beta and Hf-MOF-808 allows it to be used in the synthesis in four steps of GVL from furfural in the same reactor. Zr-MOF-808 is active and selective for the formation of arylcarbamates from aromatic amines and DMC, that is a sustainable substitute for phosgene. However, this material loses his crystallinity under the reaction conditions. Thus, in order to improve the stability of the material, Zr-MOF-808 was anchored to mesoporous silica MCM-41. The resulting Zr-MOF-808@MCM-41 was active and selective in the formation of arylcarbamates, precursors of polyurethanes, from diamines and DMC. In addition, the material can be reused up to 6 times without significant loss of activity. The use of SiO2 is also viable as a support, being much cheaper than the MCM-41. / Rojas Buzo, S. (2019). Síntesis de materiales porosos metal-orgánicos y su aplicación en catálisis heterogénea [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/130208 / TESIS

Σκοπός: Ο προσδιορισμός των επιπέδων συγκέντρωσης καταλοίπων κτηνιατρικών παρασιτοκτόνων ουσιών (ανθελμινθικών), σε νωπό γάλα μηρυκαστικών από περιοχές της Νοτίου Ελλάδος και η εκτίμηση της πρόσληψής τους από τον άνθρωπο. Συγκεκριμένα εξετάσθηκαν οι ουσίες, Albendazole, Febantel, Fenbendazole, Mebendazole και κάποιοι μεταβολίτες τους (Albendazole sulfoxide, Albendazole sulfone, Fenbendazole sulfone) στο νωπό γάλα προβάτων, αιγών και βοοειδών. Μέθοδοι: Χημική ανάλυση δειγμάτων γάλακτος, με τη βοήθεια Υγρής Χρωματογραφίας Υψηλής Απόδοσης και ανιχνευτή Συστοιχίας Διόδων, Υπεριώδους (UV). Χρήση βάσης δεδομένων σχετικά με την εκτίμηση της ημερήσιας κατανάλωσης γάλακτος και Φέτας (λήψη προσωπικών συνεντεύξεων, συμπλήρωση ερωτηματολογίων, συχνοτήτων κατανάλωσης τροφίμων, από δείγμα 723 μαθητών ηλικίας 10-12 ετών, από τη Νότια Ελλάδα). Αποτελέσματα: 34 από τα 123 δείγματα γάλακτος βρέθηκαν να περιέχουν κατάλοιπα των διερευνώμενων ουσιών, εκ των οποίων τα 11 υπερέβαιναν τα θεσπισμένα από την Ε.Ε. ανώτατα επιτρεπτά όρια καταλοίπων. Η Εκτιμώμενη Ημερήσια Πρόσληψη των ουσιών αυτών, από το εξετασθέν δείγμα πληθυσμού, κυμαίνεται από 0,4-15,9% της Αποδεκτής Ημερήσιας Πρόσληψης, ανάλογα με την ουσία και το τρόφιμο (νωπό αγελαδινό γάλα ή τυρί Φέτα). Υπάρχει γεωγραφική διακύμανση στη συχνότητα εμφάνισης των καταλοίπων η οποία είναι ιδιαίτερα αυξημένη σε περιοχές οι οποίες στερούνται επαρκών υπηρεσιών ελέγχου τροφίμων. Συμπεράσματα: Από την παρούσα εργασία προκύπτει ότι 11.4% των δειγμάτων γάλακτος, περιέχει κατάλοιπα ανθελμινθικών ουσιών, σε επίπεδα συγκεντρώσεων που υπερβαίνουν το ανώτατο επιτρεπτό όριο (έως και 7 φορές για τη Febantel). Το εύρημα αυτό, εγείρει ερωτήματα για την πλήρη εφαρμογή της Ο.Κ.Π.. Ωστόσο η κατανάλωση νωπού γάλακτος το οποίο περιέχει κατάλοιπα των υπό διερεύνηση ενώσεων, στα προαναφερθέντα επίπεδα συγκεντρώσεων, δεν οδηγεί σε υπέρβαση της Ανώτερης Ημερήσιας Πρόσληψης. Από την άλλη πλευρά, είναι απαραίτητο να τονιστεί ότι οι ουσίες αυτές είναι δυνατό να ανιχνευθούν και σε άλλα τρόφιμα ζωικής προέλευσης για τα οποία δεν έχουν θεσπιστεί MRLs και συνεπώς δε διεξάγονται οι αντίστοιχοι έλεγχοι. Κατά συνέπεια, είναι απαραίτητη η εκπαίδευση των κτηνοτρόφων σε θέματα Ο.Κ.Π., η εντατικοποίηση των ελέγχων και η στελέχωση των κρατικών υπηρεσιών, έτσι ώστε να αντισταθμίζονται οι ελλείψεις των νόμων και να αποφευγονται πιθανές δυσμενείς συνέπειες για τη δημόσια υγεία. / Aim: The determination of the concentration levels, of veterinary parasiticide drug (anthelmintics) residues, in ruminants’ raw milk, from regions of Southern Greece, and the residues’ intake estimation for humans. In particular, the investigated, residues were Albendazole, Febantel, Fenbendazole, Mebendazole and some of their metabolites (Albendazole sulfoxide, Albendazole sulfone, Fenbendazole sulfone), in sheep, goat and bovine raw milk. Methods: Chemical analysis of raw milk samples with High Performance Liquid Chromatography and UV Diode Array Detector. A databank concerning the daily consumption of milk and feta cheese was utilized (personal interviews and filling in of food frequency questionnaires, from a population sample of 723 pupils aged from 10-12 years old, in Southern Greece). Results: 34 out of the 123 milk samples, were found to contain residues of the investigated compounds and 11 of the contaminated samples, contained residues, exceeding the EU established MRLs. The Estimated Daily Intake for these residues resulting from the interviewed population sample, was ranging from 0,4 to 15,9% of the Acceptable Daily Intake, depending on the substance and the kind of food (raw bovine milk or feta cheese). There is a geographical variation concerning the residue occurrence, which is high in regions where food control agencies are poorly staffed. Conclusions: The present study indicates that 11.4% of milk samples analysed, contains concentration levels of anthelmintic residues above the maximum residue limit (up to 7 times for Febantel). This finding raises questions about the full implementation of Good Veterinary Practice. However, consumption of raw milk containing the aforementioned concentration levels of the compounds under investigation, does not result to exceedance of the Acceptable Daily Intake. On the other hand, it is necessary to emphasize that these substances are possible to be detected in other foods of animal origin for which no MRLs have been established and therefore the respective controls are not carried out. Consequently, training of stock-farmers on GVP, intensification of controls and staffing of government agencies, are needed to counterbalance deficiencies of laws and avoid potential adverse effects on public health.