Academic literature on the topic 'Quinoxalinona'

The 3-methyl group in quinoxalinones I and II has been found to undergo diformylation by Vilsmeier reagent to give the corresponding aminoacrolein derivatives (III, IV). Condensation and/or interaction of III or IV with some secondary heterocyclic amines and/or with hydrazine, phenylhydrazine and hydroxylamine affords the related 3-methyl-N-(1H)-2-quinoxalinone and 1,3-dimethyl-2-quinoxalinone derivatives (VII-XVIII), some with pronounced fluorescence activities. All synthesized compounds have been screened in vitro for their antimicrobial activities against Gram-positive and Gram-negative bacteria. The structures of these compounds were confirmed by elemental analysis, IR and 1H NMR spectroscopy.

Quinoxalinone and its derivatives are used in organic synthesis for building natural and designed synthetic compounds and they have been frequently utilized as suitable skeletons for the design of biologically active compound. This review covers updated information on the most active quinoxalinone derivatives that have been reported to show considerable pharmacological actions such as antimicrobial, anti-inflammatory, antidiabetic, antiviral, antitumor, and antitubercular activity. It can act as an important tool for chemists to develop newer quinoxalinone derivatives that may prove to be better agents in terms of efficacy and safety.

The title compound, C16H19N5O, is built up from a planar quinoxalinone ring system linked through a methylene bridge to a 1,2,3-triazole ring, which in turn carries ann-butyl substituent. The triazole ring is inclined by 67.09 (4)° to the quinoxalinone ring plane. In the crystal, the molecules form oblique stacks along thea-axis direction through intermolecular C—HTrz...NTrz(Trz = triazole) hydrogen bonds, and offset π-stacking interactions between quinoxalinone rings [centroid–centroid distance = 3.9107 (9) Å] and π–π interactions, which are associated pairwise by inversion-related C—HDhydqn...π(ring) (Dhydqn = dihydroquinoxaline) interactions. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H...H (52.7%), H...N/N...H (18.9%) and H...C/C...H (17.0%) interactions.

An efficient oxidative dehydrogenative coupling of quinoxalinones and pyrazolones has been successfully developed using a readily available persulfate oxidant. This protocol provides facile access to a wide array of hydroxy-pyrazolyl quinoxalinones in good to excellent yields.

A hexaazatriphenylene (HAT) derivative, naphtho[2,3-h]naphtho[2′,3′:7,8]quinoxalino[2,3-a]naphtho[2′,3′:7,8]quinoxalino[2,3-c]phenazine-5,10,15,20,25,30-hexaone (NQH) was synthesized, characterized, and found to be selective to copper (Cu²⁺) ions.

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This work describes the synthesis of a number of polyaza heterocycles and the mechanistic study to obtain these products. Furthermore, the characterization was performed by spectroscopic method and the structural study by X-ray diffraction and theoretical calculations of molecular orbitals. The synthesis of polyaza heterocyclic compounds began from the cyclocondensation reaction between a β- enaminodiketone and 2-aminopyridine, 2-aminothiazole or 2-aminobenzoimidazole in order to achieve pyrido[1,2-a]pyrimidin-4-one, thiazole[3,2-a]pyrimidin-5-one or 2- oxo-pyrimido[1,2-a]benzimidazole, respectively, with a α-keto ester substituent, in high regioselectivity. The mechanistic proposal developed in this step is based on the semi-empirical theoretical calculations by the PM3 method. From these data it was possible to say that the reaction was controlled by frontier molecular orbital, according to values of HOMO/LUMO coefficient obtained for the reactants. In the next step, the α-keto esters previously obtained, were reacted with ethylenediamine and derivatives ledding to the pyrazinones formation and the reaction with 1,2- phenylenediamine and derivatives led to the formation quinoxalinones. The same reaction of α-keto esters with amidines did not lead to the formation of imidazolonas as expected, since only the formation of the substitution product in the ester group occurred. The reaction mechanisms proposed in these steps are also based in theoretical calculations, where it was possible to infer that the reaction was thermodynamically controlled, since the reactivity sites were less important than the stability of the intermediates. The compounds were characterized by 1D nuclear magnetic resonance experiments of such as 1H and 13C and 2D such as COSY, HETCOR and HMBC, besides of mass spectrometry. The molecular structural studies by X-ray diffraction (for the compounds that could be measured) revealed that polyaza heterocycles pyrido[1,2-a]pyrimidin-4-one, thiazole[3,2-a]pyrimidin-5-one and 2-oxo-pyrimido[1,2-a]benzimidazole are essentially plane. All these compounds showed as pattern at least one intramolecular interaction between a carbonyl oxygen atom and a carbonyl carbon via π-hole, forming a five membered pseudo-ring, which stabilizes the position of a carbonyl group. The study revealed that all structural supramolecular compounds exhibit a large number of weak hydrogen bonds of the type CH···X (where X = O, N) and the compounds which exhibited a NH group in its structure or water in the asymmetric unit formed additionally strong hydrogen bonds of the type X-H···X (where X = O, N). Since the structures studied are aromatic heterocycles, all compounds showed interactions involving π systems in their interactions like π···π and/or lone-pair···π in their crystal packing. Only one intermolecular interaction via σ-hole (C=O···S) and another via π-hole (C=O···C=O) were found.
Neste trabalho é descrita a síntese de uma série de poliaza heterociclos e o estudo mecanístico para a obtenção destes produtos. Além disso, é realizada sua caracterização utilizando métodos espectroscópicos e o estudo estrutural por difração de Raios-X e cálculos teóricos de orbitais moleculares. A síntese dos compostos poliaza heterocíclicos teve inicio a partir de reações de ciclocondensação entre uma β-enaminodicetona e 2-aminopiridina, 2-aminotiazol ou 2-aminobenzoimidazol para obter pirido[1,2-a]pirimidin-4-ona, tiazolo[3,2-a]pirimidin-5- ona e 2-oxo-pirimido[1,2-a]benzoimidazol, respectivamente, com um substituinte α- ceto éster, de maneira altamente regiosseletiva. A proposta mecanística elaborada nesta etapa está embasada em cálculos teóricos semi-empíricos pelo método PM3. A partir destes dados é possível afirmar que a reação é controlada por orbital molecular de fronteira, conforme os valores de coeficiente de HOMO/LUMO obtidos para os reagentes. Na etapa seguinte, os α-ceto ésteres, previamente obtidos, ao reagirem com etilenodiamino e derivados levaram a formação de pirazinonas, bem como, a reação com 1,2-fenilenodiamino e derivados levou a formação de quinoxalinonas como produto. A reação dos mesmos α-ceto ésteres com amidinas não levou a formação de imidazolonas como desejado, pois ocorreu apenas a formação do produto de substituição no grupo éster. Os mecanismos de reação propostos nestas etapas também estão embasados em cálculos teóricos, onde foi possível inferir que a reação foi termodinamicamente controlada, já que, a reatividade dos sítios foi menos importante que a estabilidade dos intermediários. Os compostos foram caracterizados utilizando ressonância magnética nuclear em experimentos de 1D como 1H e 13C, e 2D como COSY, HETCOR e HMBC, além de espectrometria de massas. O estudo estrutural molecular por difração de Raios-x (referente aos compostos que puderam ser medidos) revelou que os poliaza heterociclos pirido[1,2- a]pirimidin-4-ona, tiazolo[3,2-a]pirimidin-5-ona e 2-oxo-pirimido[1,2-a]benzoimidazol são essencialmente planos. Um padrão observado nestes compostos é que todos apresentam, pelo menos, uma interação intramolecular entre um átomo de oxigênio carbonílico e um carbono carbonílico via π-hole, formando um pseudo-anel de cinco membros, que estabiliza a posição de uma carbonila. O estudo estrutural supramolecular revelou que todos os compostos apresentam um amplo número de ligações de hidrogênio fracas do tipo C-H· · ·X (quando, X = O, N) e os compostos que apresentaram um grupo N-H em sua estrutura ou água na unidade assimétrica formam, adicionalmente, ligações de hidrogênio fortes do tipo X-H···X (quando, X = O, N). Como as estruturas estudadas apresentam heterociclos aromáticos, todos os compostos mostraram interações envolvendo seus sistemas π em interações do tipo π· · ·π e/ou lone-pair· · ·π em seus empacotamentos cristalinos. Apenas uma interação intermolecular via σ-hole (C=O· · ·S) e uma via π-hole (C=O· · ·C=O) foram encontradas.

This work describes the synthesis and functionalization of azoles employing different methodologies, based on organometallic catalysis or not. Firstly, we disclose the synthesis tetra-substituted 5-trifluoromethyl pyrazoles via sequential halogenation of 5-trifluoromethyl pyrazoles and palladium-catalyzed carbon–carbon and carbon–nitrogen cross-coupling reactions employing organozinc reagents and amines as coupling partners, respectively. This work allowed to achieve new pyrazolic systems in moderated to good yields. Posteriorly, we show the synthesis of 1,3-di(hetero)aryl indazoles exploring the complementary catalytic activity of nickel and copper complexes. We commenced this study evaluating different nickel pre-catalysts to perform the intramolecular amination of unprotected 2-chlorophenyl hydrazones. In a second moment, we described the N-(hetero)arylation of the in situ generated NH indazoles, using a simple catalytic system based on copper/DMEDA. This sequential one-pot fashion procedure allowed the achievement of several 1,3-di(hetero)aryl indazoles in moderate to good yields. Lastly, we disclose the formation of pyrazolo[1,5-a]quinoxalin-4(5H)-ones by the reaction between ethyl 1-(2-chlorophenyl)-1H-pyrazole-5-carboxylate and primary amines. The one-pot methodology undergoes by two sequential reactional pathways: i) amidation of the ester moiety attached to the pyrazole ring, and ii) intramolecular cyclization via nucleophilic aromatic substitution. This synthetic approach proved to be efficient only for primary aliphatic amines, allowing to achieve molecules with different substitution patterns in moderate to good yields. Key-words: Azoles, quinoxalinones, Negishi cross-coupling, Buchwald-Hartwig cross-coupling.
Este trabalho descreve a síntese e a funcionalização de azóis através de diferentes metodologias, ancoradas ou não na catálise organometálica. Primeiramente, descrevemos a síntese de 5-trifluormetil pirazóis tetrassubtituídos através de reações de acoplamento cruzado catalisadas por complexos de paládio entre 5-trifluormetil-4-halo pirazóis, reagentes organozinco e aminas. Este trabalho permitiu a obtenção de novos sistemas pirazólicos com rendimentos moderados a bons. Posteriormente realizamos a síntese de 1,3-di(hetero)aril indazóis explorando as atividades catalíticas complementares de complexos de níquel e cobre. Primeiramente avaliamos diferentes pré-catalisadores de níquel para realizar a aminação intramolecular de diferentes 2-clorofenil hidrazonas não protegidas. Em um segundo momento, realizamos a N-(hetero)arilação dos NH indazóis gerados in situ, através do emprego de um sistema catalítico baseado em cobre/DMEDA. A metodologia permitiu a obtenção de diferentes indazóis 1,3-di(hetero)aril substituídos, com rendimentos moderados a bons. Por fim, demonstramos a síntese de pirazolo[1,5-a]quinoxalin-4(5H)-onas a partir da reação entre 1-(2-clorofenil)-1H-pirazolo-5-carboxilatos de etila e aminas primárias. A metodologia one-pot envolve duas etapas sequenciais; i) amidação da função éster do pirazol e ii) ciclização intramolecular via substituição nucleofílica aromática. Esta abordagem sintética provou ser eficiente ao se empregar aminas alquílicas primárias, permitindo a obtenção de diferentes padrões de substituição com rendimentos moderados a bons.

Depuis quelques décennies, l’étude de systèmes biologiques complexes est un domaine en plein essor. Ainsi, des outils de ligation des biomolécules avec des reporters chimiques ont été mis en place afin d’avoir une compréhension toujours fine du vivant. Les ligations sont des réactions chimiques biocompatibles permettant de lier deux entités synthétiques ou biologiques entre elles. On regroupe généralement ces ligations en deux catégories, les réactions de bioconjuguaison, qui font intervenir des fonctions chimiques naturellement présentes dans les biomolécules, et les réactions bio-orthogonales qui n’interfèrent pas avec les fonctions chimiques présentes dans ces milieux, mais nécessitent en amont une modification des partenaires de réaction. Cependant, il convient de faire la distinction avec une troisième catégorie, les réactions de conjugaison chimiosélectives, qui mettent en oeuvre des fonctions non naturellement présentes sur les biomolécules. En ce sens, elles se rapprochent donc des réactions bio-orthogonales, mais les fonctions ou conditions mises en jeu ne sont pas suffisamment bio-orthogonales ou les réactions ne sont pas suffisamment rapides pour pouvoir être réalisées dans les systèmes biologiques. Ces ligations sont toutefois très utilisées pour de la construction biomoléculaire allant de la petite molécule (par exemple oligopeptide modifié) à la biomacromolécule (type protéine modifiée) et se distinguent par une facilité de mise en oeuvre et purification des conjugués, ce qui n’est pas toujours réa lisable avec l’arsenal des réactions bio-orthogonales qui conduisent à la formation de multiple isomères. Ainsi, mes travaux de thèse se sont orientés vers la découverte et/ou l’étude de ligations chimiosélectives ainsi qu’à leur utilisation dans la préparation de sondes fluorescentes voire fluorogéniques. L’étude de la ligation Kondrat’eva préalablement développée au sein du laboratoire, a permis de mettre en évidence son caractère fluorogénique, et a été exploitée pour le marquage fluorescent de molécules via une étape unique de ligation fluorogénique. Puis, le développement d’une ligation utilisant le système tétrazine/pyrazolone a été développée afin de pallier le manque de sélectivité des réactions basées sur le motif tétrazine proposées jusqu’alors, qui conduisent aux bioconjugués sous la forme d’un mélange de produits. Cette approche a été illustrée par le marquage fluorescent d’une protéine humaine. Enfin, le développement d’une nouvelle voie d’accès aux quinoxalinones a permis leur étude photophysique et la mise en évidence de propriétés fluorogéniques utilisées notamment pour la synthèse d’une biosonde
In recent decades, the study of complex biological systems has been a growing field. Thus, biomolecules ligation tools with chemical reporters were set up in order to have a better and fine understanding of the living. Ligations are biocompatible chemical reactions that link two synthetic or biological entities one antother. These ligations are generally gathered into two categories, bioconjugation reactions, using chemical functions naturally present in the biomolecules, and bio-orthogonal reactions which does not interfere with these function, but require a prior engineering of the biological partner. However, it is necessary to distinguish a third category, the chemoselective conjugation reactions, which implement functions not naturally present on biomolecules. In this sense, they are therefore closer to bio-orthogonal reactions, but the functions or conditions involved are not sufficiently bioorthogonal or the reactions are not fast enough to be carried out in any biological systems. These ligations are, however, widely used for biomolecular constructions ranging from the small molecule (for example modified oligopeptides) to the biomacromolecule (protein modification) and are distinguished by their ease of implementation and purification of the conjugates, which is not always feasible with the arsenal of bio-orthogonal reactions that leads to the formation of multiple isomers. Thus, my PhD work focused on the discovery and / or the study of chemoselective ligations as well as their use in the preparation of fluorescent or fluorogenic probes. The study of the Kondrat'eva ligation previously developed within the laboratory, highlighted its fluorogenic behaviour, and was exploited for the fluorescent labelling of molecules through a single fluorescence-ligation step. Then, the development of a ligation using the tetrazine / pyrazolone system was developed in order to overcome the lack of selectivity of the reactions based on the tetrazine scaffold which often lead to the formation of bioconjugates as a mixture of isomers. This approach has been illustrated by the fluorescent labelling of a human protein. Finally, the development of a new access route to quinoxalinones allowed to study their photophysical properties and to highlight their fluorogenic properties which were leveraged in particular for the synthesi s of a bioprobe

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Gliomas are the most common and devastating tumors of the central nervous system (CNS). Among the gliomas group, the GBM is the most prevalent, aggressive and deadly malignant. Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. Chalcones are group of natural precursors of flavonoid and display a wide variety of biological and pharmacological proprieties that include anti-proliferative and anti-cancer activities. This study aimed at evaluating the in vitro anti-proliferative activity and cell viability inhibition of nine quinoxaline derived chalcones, structurally based on the selective PI3Ky inhibitor AS605240. These synthetic compounds were tested at different time-periods of incubation (24, 48 e 72 h) and concentrations (0,1; 0,1; 1; 5 e 10 μg/mL) in glioma cell lines from human and rat origin (U-138 MG and C6, respectively).The results showed by MTT assay and cell couting revealed that four chalcones (compounds N2, N9, N10 and N12), displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration dependent manner. These four compounds which present methoxy groups at A-ring and their efficacy was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with chalcone N9 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, chalcone N9 was able to visibly inhibit AKT activation, allied to the stimulation of ERK 1/2 MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent at A-ring, might well represent promising molecules for the treatment of gliomas.
Os gliomas são os tumores do SNC mais comuns e devastadores. Dentre os gliomas, o GBM é o mais prevalente, agressivo, maligno e apresenta um mau prognóstico. A relevância dos compostos naturais, incluindo as chalconas, no tratamento e na prevenção do câncer está sendo muito evidenciada. As chalconas formam um grupo de compostos naturais derivados dos flavonóides que apresentam diferentes propriedades biológicas e farmacológicas, incluindo as atividades anti-proliferativas e anti-tumorais. O objetivo deste estudo foi avaliar a ação anti-proliferativa e a capacidade de inibição da viabilidade celular in vitro de nove chalconas derivadas da quinoxalina, baseadas estruturalmente no inibidor seletivo de PI3Ky, o AS605240. Estes compostos sintéticos foram testados em diferentes tempos de incubação (24, 48 e 72 h) e concentrações (0,1; 0,1; 1; 5 e 10 μg/mL) em linhagens de glioma humano e de rato (U-138 MG e C6, respectivamente). Os resultados observados nos experimentos de MTT e na contagem celular revelaram que quatros chalconas (compostos N2, N9, N10 e N12), apresentaram grande eficácia e potência, sendo capazes de inibir a proliferação e a viabilidade celular, de maneira tempo e concentração dependente. Estes quatro compostos que possuem radicais metóxi no anel A de sua estrutura demonstraram uma eficácia superior àquela do composto AS605240, usado como controle positivo. Os resultados da citometria de fluxo demonstraram que a incubação das células C6 com a chalcona N9 levaram a um bloqueio celular na fase G1, possivelmente indicando interferência com a apoptose. Além disto, a chalcona N9 foi capaz de inibir visivelmente a ativação da AKT, aliada à estimulação de ERK 1/2 MAP-quinase. As chalconas estudadas neste projeto, especialmente as que apresentam o radical metoxi no anel A, representam promissoras moléculas para o tratamento dos gliomas.

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Gliomas are the most common and devastating tumors of the central nervous system (CNS). Among the gliomas group, the GBM is the most prevalent, aggressive and deadly malignant. Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. Chalcones are group of natural precursors of flavonoid and display a wide variety of biological and pharmacological proprieties that include anti-proliferative and anti-cancer activities. This study aimed at evaluating the in vitro anti-proliferative activity and cell viability inhibition of nine quinoxaline derived chalcones, structurally based on the selective PI3Ky inhibitor AS605240. These synthetic compounds were tested at different time-periods of incubation (24, 48 e 72 h) and concentrations (0,1; 0,1; 1; 5 e 10 μg/mL) in glioma cell lines from human and rat origin (U-138 MG and C6, respectively). The results showed by MTT assay and cell couting revealed that four chalcones (compounds N2, N9, N10 and N12), displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration dependent manner. These four compounds which present methoxy groups at A-ring and their efficacy was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with chalcone N9 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, chalcone N9 was able to visibly inhibit AKT activation, allied to the stimulation of ERK 1/2 MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent at A-ring, might well represent promising molecules for the treatment of gliomas.
Os gliomas s?o os tumores do SNC mais comuns e devastadores. Dentre os gliomas, o GBM ? o mais prevalente, agressivo, maligno e apresenta um mau progn?stico. A relev?ncia dos compostos naturais, incluindo as chalconas, no tratamento e na preven??o do c?ncer est? sendo muito evidenciada. As chalconas formam um grupo de compostos naturais derivados dos flavon?ides que apresentam diferentes propriedades biol?gicas e farmacol?gicas, incluindo as atividades anti-proliferativas e anti-tumorais. O objetivo deste estudo foi avaliar a a??o anti-proliferativa e a capacidade de inibi??o da viabilidade celular in vitro de nove chalconas derivadas da quinoxalina, baseadas estruturalmente no inibidor seletivo de PI3Ky, o AS605240. Estes compostos sint?ticos foram testados em diferentes tempos de incuba??o (24, 48 e 72 h) e concentra??es (0,1; 0,1; 1; 5 e 10 μg/mL) em linhagens de glioma humano e de rato (U-138 MG e C6, respectivamente). Os resultados observados nos experimentos de MTT e na contagem celular revelaram que quatros chalconas (compostos N2, N9, N10 e N12), apresentaram grande efic?cia e pot?ncia, sendo capazes de inibir a prolifera??o e a viabilidade celular, de maneira tempo e concentra??o dependente. Estes quatro compostos que possuem radicais met?xi no anel A de sua estrutura demonstraram uma efic?cia superior ?quela do composto AS605240, usado como controle positivo. Os resultados da citometria de fluxo demonstraram que a incuba??o das c?lulas C6 com a chalcona N9 levaram a um bloqueio celular na fase G1, possivelmente indicando interfer?ncia com a apoptose. Al?m disto, a chalcona N9 foi capaz de inibir visivelmente a ativa??o da AKT, aliada ? estimula??o de ERK 1/2 MAP-quinase. As chalconas estudadas neste projeto, especialmente as que apresentam o radical metoxi no anel A, representam promissoras mol?culas para o tratamento dos gliomas.

La détection et l'imagerie par fluorescence de systèmes biologiques nécessite la mise en place d'outils efficaces, robustes et simples d'utilisation. Les sondes fluorogéniques conventionnelles, actuellement utilisées en microbiologie manquent de précision puisqu'elles résultent de la simple modification chimique de la structure d'un fluorophore déjà formé, conduisant souvent à une extinction incomplète de sa fluorescence intrinsèque. Mes travaux de thèse ont pour but de développer de nouveaux substrats fluorogéniques d'enzymes basés sur le principe du "covalent assembly". Cette approche de synthèse chimique in situ d'un cœur fluorescent à partir d'un précurseur dit "cagé" non-fluorescent, met en jeu des réactions domino caractérisées par la formation et la rupture de liaisons covalentes, déclenchées par une réaction enzymatique déclenchée par les bactéries à identifier. Les avantages d'une telle approche sont nombreux (meilleur rapport signal sur bruit, exemplification aisée à un large éventail d'analytes, …). Dans ce contexte, le premier objectif de ma thèse a été de synthétiser des fluorophores de type hétéro-xanthène originaux afin de valider leur stabilité dans des conditions physiologiques. De nouvelles sulfone- et Si-pyronines ont été obtenus. La synthèse des précurseurs "cagés" correspondant aux composés les plus stables en milieux aqueux, a été entreprise pour pouvoir les utiliser comme sondes à peptidases. L'ensemble de ces travaux sont décrits dans le chapitre I et II de ce manuscrit. Les difficultés rencontrées lors de la mise en œuvre de l'approche "covalent assembly" avec ces hétéro-xanthènes, nous ont conduit à explorer une nouvelle famille de fluorophores, les quinoxalinones. La formation in-situ de ces hétérocycles fluorescents, faisant suite à un stimuli enzymatique d'un précurseur "cagé" est présenté dans le chapitre III. Enfin le dernier chapitre traite de la synthèse d'une sonde conventionnelle dérivée d'une bis-sulfonyle-bis-aniline récemment publiée dans la littérature
Detection and fluorescence imaging of biologic systems requires the implementation of efficient, robust and easy-to-use tools. Conventional fluorogenic probes currently used in microbiology lack efficiency since they are based on the single chemical modification of a fluorophore bearing an optically tunable reactive group, which often leads to incomplete fluorescence quenching. The main goal of my Ph.D thesis was to develop novel fluorogenic enzymatic substrates based on the "covalent assembly" principle. This approach also named "in situ synthesis" is based on the use of domino reactions to form a fluorescent moiety starting from a "caged" non-fluorescent molecule. In our case, the bioanalyte that triggers the reaction is present in bacteria, that we want to detect. This strategy provides many advantages (improved signal-to-noise ratio, easy exemplification to a wide range of analytes, …). In this context, the first goal of my thesis was to synthesize original fluorescent hetero-xanthene dyes to assess their stability under physiological conditions. Novel sulfone- and Si-pyronin derivatives were obtained. Synthesis of the corresponding "caged" precursors to the most stable compounds was then undertaken for their use as a peptidase-responsive probes. This work is described in the first and second chapter of this manuscript. Faced with difficulties to implement "covalent assembly" probe design principle to Si-pyronins, another class of fluorophores, namely quinoxalinone was explored. In situ formation of these fluorescent heterocycles triggered by an enzyme is presented in the third chapter. Finally, the last chapter was devoted to the synthesis of a conventional probe derived from a bis-sulfonyl-bis-aniline recently reported in the literature

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The synthesis of some sampangine analogs was accomplished by using suitable natural and synthetic quinones, namely lapachol and nor-lapachol. These readily available compunds were functionalized by a sequence of O-methylation using dimethylsulfate in basic media, and chemoselective nucleophylic displacement with 2-aminoethanol and 3-aminopropanol. Further transformation of hydroxyl group in azide by a sequence involving tosylation results in the key intermediates. These 2-amino-ω-azido compunds were submitted to catalytic hydrogenation over palladium on charcoal yielding the corresponding quinoxaline and 1,4-diazepine nucleus. Some of these compounds were sequentially cyclized with the aid of DDQ to yield the corresponding tetracyclic analogs of sampagine alkaloids. All compounds were characterized by usual methods including proton and carbon-13 NMR, infrared.
Partindo-se de quinonas naturais e sintéticas facilmente disponíveis em nosso laboratório foi sintetizada uma série de 2-amino-quinonas intermediárias e derivados cíclicos nitrogenados, sendo alguns inéditos na literatura. Assim, a partir das 2-hidroxi-quinonas, lapachol e nor-lapachol obteve-se os correspondentes derivados 2-metoxilados via alquilação com sulfato de dimetila em meio básico. A seguir reagiram quimiosseletivamente com 2-etanolamina e 3-propanolamina, formando os amino-álcoois correspondentes. Através da sequência de tosilação seguida de substituição nucleofílica com azida de sódio, obteveram-se os azido compostos correspondentes, os quais são os intermediários-chave na síntese de análogos cíclicos do alcalóide natural quinonóide sampangina. Os azidos compostos, deram origem a novas quinoxalinas e diazepinas, quando submetidos a hidrogenação catalítica usando-se paládio sobre carvão que oxidadas com DDQ permitiram a ciclização da cadeia lateral prenílica originando um novo composto tetracíclico análogo da sampangina. Os rendimentos globais obtidos variaram de 58 a 91%. Os compostos foram caracterizados por espectroscopia de RMN 1H, RMN 13C, IV.

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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES)
A s?ntese de compostos heteroc?clicos, tais como derivados de quinoxalina, tem se mostrado bastante relevante e promissora devido ?s diversas aplica??es verificadas nas ?reas biol?gicas e tecnol?gicas. Este trabalho dedicou-se a s?ntese, caracteriza??o e reatividade de derivados quinoxal?nicos a partir de dois precursores sint?ticos: o ?cido-L-asc?rbico (1) e do bloco de constru??o 2,3-dicloro-6,7-dinitroquinoxalina (2). A partir da s?ntese e caracteriza??o dos compostos derivados do ?cido-L-asc?rbico (1) foram realizados estudos visando sua aplica??o como quimiossensores, no qual o composto 36 demonstrou-se seletivo para o ?on Cu2+, em metanol, mediante an?lises colorim?trica e por espectroscopia UV-vis?vel. Al?m disto, an?lises iniciais sugerem que o composto 39 derivado de 36, uma base de Schiff, tamb?m apresenta caracter?sticas de quimiossensor para o mesmo metal. A partir do composto 2, foram sintetizados cinco compostos atrav?s de rea??es de substitui??o nucleof?lica arom?tica com aminas alif?ticas. O controle das condi??es experimentais permitiu a obten??o tanto de produtos mono- quanto dissubstitu?dos. Estudos de reatividade foram realizados com dois prop?sitos: i) investigar a possibilidade de atua??o do composto 47 como quimiossensor para ?nions, a partir da rea??o com hidr?xido de s?dio em DMSO, atrav?s dos resultados obtidos pela an?lise de imagem e espectroscopia UV-vis?vel; ii) caracterizar cineticamente a convers?o do composto 44 em 46 atrav?s da an?lise de imagens pelos m?todos RGB e multivariada a partir de dados de CCD, mostrando-se uma ferramenta simples e de baixo custo para an?lises qualitativas e quantitativas.
Synthesis of heterocyclic compounds, as quinoxaline derivatives, has being shown to be relevant and promissor due to expressive applications in biological and technological areas. This work was dedicated to the synthesis, characterization and reactivity of quinoxaline derivatives in order to obtain new chemosensors. (L)-Ascorbic acid (1) and 2,3-dichloro-6,7- dinitroquinoxalina (2) were explored as synthetic precursors. Starting from synthesis of 1 and characterization of compounds derived from (L)-ascorbic acid, studies were performed investigating the application of products as chemosensors, in which compound 36 demonstrated selective affinity for Cu2+ ?ons in methanolic solution, by naked-eye (colorimetric) and UVvisible analyses. Further, initial analysis suggests that 39 a Schiff?s base derived from 36 also presents this feature. Five quinoxaline derivatives were synthesized from building block 2 through nucleophilic aromatic substitution by aliphatic amines, in which controlling the experimental conditions allows to obtain both mono- and di-substituted derivatives. Reactivity studies were carried out with two purposes: i) investigate the possibility of 47 compound being a chemosensor for anion, based on its interaction with sodium hydroxide in DMSO, using image analysis and UV-visible spectroscopy; ii) characterize kinetically the conversion of compound 44 into 46 based on RGB and multivariate image analysis from TLC data, as a simple and inexpensive qualitative and quantitative tool.