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1	Síntese e avaliação da atividade antimicrobiana de 3-aril-2-isoxazolina [5,4-d]pirrolidinas na forma de base livre e de seus sais cloridratos SANTOS, Adriano Carlos Vieira dos 30 May 2014 (has links) Submitted by Ramon Santana (ramon.souza@ufpe.br) on 2015-03-10T18:47:31Z No. of bitstreams: 2 DISSERTAÇÃO Adriano Carlos Vieira dos Santos.pdf: 4334924 bytes, checksum: fb764c055d3256c9ebc2045d717205ac (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-03-10T18:47:31Z (GMT). No. of bitstreams: 2 DISSERTAÇÃO Adriano Carlos Vieira dos Santos.pdf: 4334924 bytes, checksum: fb764c055d3256c9ebc2045d717205ac (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2014-05-30 / A química medicinal é uma ferramenta importantíssima para o planejamento e o desenvolvimento de moléculas orgânicas, a fim de verificar as possíveis atividades biológicas destas. Dentre as inúmeras classes de compostos orgânicos, tem ganhado muito destaque o núcleo isoxazolínico, especialmente a 2-isoxazolina, devido a sua ampla utilização não só nas áreas cientificas, mas também tecnológica. O núcleo isoxazolínico vem sendo obtido, na grande maioria das vezes, através das reações de cicloadição do tipo 1,3-dipolar. Nestas reações, duas espécies químicas envolvidas, um dipolo e um dipolarófilo, reagem entre si através de seus orbitais de fronteira, HOMO e LUMO, formando-se então o núcleo 2-isoxazolina – heterociclo de cinco membros. No estudo utilizaram-se como dipolarófilos os enecarbamatos endocíclicos de cinco membros 41 e 43, obtidos pelo método da sonicação em um curto intervalo de tempo, e como dipolos os óxidos de nitrila 37 formados a partir da cloração das aril-oximas com NCS. As aril-oximas, por sua vez, foram obtidas a partir dos respectivos benzaldeídos para-substituídos com rendimentos entre 93 e 95%. Obtiveram-se nas reações de cicloadição 1,3-dipolar, realizadas a temperatura ambiente, rendimentos entre 42 e 77%. O cicloaduto 44b, resultante da reação de cicloadição, após sua purificação foi submetido à hidrogenólise em meio ácido, obtendo-se então os cloridratos de isoxazolina aril substituídos 46 com rendimento entre 53 e 64%. Estes, após basificação com solução aquosa de bicarbonato de sódio, foram transformados em suas respectivas aril isoxazolinas na forma de base livre em N6 45, apresentando rendimento quantitativo. Dentre as atividades biológicas relatadas na literatura, inúmeros estudos mostram a 2-isoxazolina como bons agentes anti-inflamatórios, antitumorais, antivirais e com grande destaque para a atividade antimicrobiana, através de testes realizados em bactérias e fungos. Sendo assim, as séries de moléculas obtidas 45 e 46 foram testadas contra bactérias gram positivas e gram negativas através do método de difusão em disco para averiguar a atividade antimicrobiana dos compostos em suas formas de aminas livres e dos seus sais de cloridratos. Neste estudo, observou-se, que boa parte dos compostos testados não exibiu expressivos valores de halos de inibição, quando comparados ao padrão utilizado, ampicilina. Teve destaque o cloridrato de aril isoxazolina p-Cloro 46b que exibiu halo de inibição de 26 mm frente à Mycobacterium smegmatis DAUFPE 71 (álcool ácido resistente), enquanto que a ampicilina apresentou para o mesmo micro-organismo apenas 14 mm de halo de inibição. Já a base livre da aril isoxazolina p-Cloro, o composto 45b, não apresentou inibição para o mesmo micro-organismo. Os demais compostos com maiores valores de halos de inibição foi o 45a frente à Escherichia coli DAUFPE 224 (12,5 mm) e M. smegmatis DAUFPE 71 (14 mm) e os compostos 45b, 46a e 46b que apresentaram halos de 11,5, 13,5 e 13,5 mm, respectivamente, contra Micrococcus luteus DAUFPE 06. 2-isoxazolina Cicloadição 1 3-dipolar Cloridratos Antimicrobianos
2	COPPER(I) CATALYZED EXO-SELECTIVE [CN+C+CC] 1,3-DIPOLAR CYCLOADDITIONS and STUDIES TOWARDS THE TOTAL SYNTHESIS OF KAITOCEPHALIN HU, JIEYU 27 May 2010 (has links) No description available. Organic Chemistry [CN+C+CC] 1
3	[en] SYNTHESIS AND MOLECULAR DOCKING OF 1,2,3-TRIAZOLES FOR THE TREATMENT OF CYSTIC FIBROSIS / [pt] SÍNTESE E ANCORAGEM MOLECULAR DE 1,2,3-TRIAZOIS PARA O TRATAMENTO DA FIBROSE CÍSTICA JOYCE FERREIRA PESSANHA DA S ROCHA 20 July 2021 (has links) [pt] Por ser uma doença genética, resultado de uma mutação em um gene específico, que gera proteínas (CFTR) defeituosas, a Fibrose Cística é uma patologia difícil de ser tratada. Os custos para os tratamentos atualmente disponíveis são altos, sem os quais, porém, a gravidade da doença tende a crescer ainda mais. Por esse motivo, novos tratamentos farmacológicos vêm surgindo, como o Trikafta (marca registrada), uma combinação tripla de fármacos com ação sinérgica (elexacaftor, ivacaftor e tezacaftor). Porém, esse medicamento ainda não é disponível no Brasil e o acesso aos tratamentos, em geral, são onerosos. Sendo assim, este trabalho visa a síntese de compostos 1,2,3-triazóis, com possível atividade biológica frente a proteína CFTR, sugerida por ancoragem molecular. Este trabalho também visa selecionar as melhores moléculas quanto aos perfis farmacocinéticos e toxicológicos, avaliados por ferramentas computacionais como swissADME e VirtualToxLab, respectivamente. Dessa forma, a estratégia sintética para a obtenção dos compostos consiste em duas etapas sintéticas. A primeira, envolve a síntese da enaminona – (E)-3-(dimetilamino)acrilaldeido (3a-d) – por organocatálise, a partir de L-prolina e DMA-DMF (1,1-dimetoxi-N,N-dimetillmetanamina) (1). A segunda etapa inclui a reação de cicloadição 1,3-dipolar onpot entre as azidas (5a-h) e as enaminonas previamente obtidas. Assim, foi possível obter 1,2,3-triazóis 1,4-substituídos (6a-k), com rendimentos de 5 a 96 por cento. Dentre eles, a molécula 6k, N-(2-(1-(4-metoxifenil)-1H-1,2,3-triazol-4-carbonil)fenil)acetamida), destacou-se quanto aos perfis toxicológicos e também pelos resultados observados nos estudos de ancoragem molecular. Os espectros de RMN de 1H e 13C RMN confirmaram a obtenção das estruturas. / [en] Because it is a genetic disease, the result of a mutation in a specific gene, which generates defective proteins (CFTR), Cystic Fibrosis is a pathology that is difficult to be treated. The costs for currently available treatments are high, without which, however, the severity of the disease tends to increase even more. For this reason, new pharmacological treatments are emerging, such as Trikafta (trademark), a triple combination of drugs with synergistic action (elexacaftor, ivacaftor and tezacaftor). However, this drug is not yet available in Brazil and access to treatments, in general, is expensive. Therefore, this work aims at the synthesis of 1,2,3-triazole compounds, with possible biological activity against the CFTR protein, proposed by molecular anchoring. This work also aims to select the best molecules in terms of pharmacokinetic and toxicological profiles, evaluated by computational tools such as swissADME and VirtualToxpot, respectively. Thus, the synthetic strategy for obtaining the compounds consists of two synthetic steps. The first involves the synthesis of enaminone - (E)-3-(dimethylamino) acrylaldehyde (3a-d) - by organocatalysis, starting from L- proline and DMA-DMF (1,1-dimethoxy-N, N-dimethylmethanamine) (1). The second stage includes the 1,3-dipolar onpot cycloaddition reaction between the azides (5a-h) and the previously obtained enaminones. Thus, it was possible to obtain 1,4-substituted 1,2,3-triazoles (6a-k), with yields of 5 to 96 percent. Among them, the molecule 6k, N- (2- (1- (4-methoxyphenyl) -1H-1,2,3-triazol-4-carbonyl) phenyl) acetamide), stood out in terms of toxicological profiles and also by results observed in molecular anchorage studies. The 1H and 13C NMR NMR spectra confirmed the structures obtained. [pt] FIBROSE CISTICA [pt] ANCORAGEM MOLECULAR [pt] ENAMINONA [pt] CICLO ADICAO 1 3-DIPOLAR [pt] IVACAFTOR [pt] 123-TRIAZOIS [pt] CFTR [en] CYSTIC FIBROSIS [en] MOLECULAR DOCKING [en] ENAMINONE [en] 1 3-DIPOLAR ADDITION CYCLE [en] IVACAFTOR [en] 123-TRIAZOLES [en] CFTR
4	New Approaches To Heterocycle Synthesis: A Greener Route To Structurally Complex Protonated Azomethine Imines, And Their Use In 1,3-Dipolar Cycloadditions Dhakal, Ram Chandra 01 January 2017 (has links) 1-Aza-2-azoniaallene salts are reactive intermediates that undergo [3+2] cycloaddition with many different types of multiple bonds. For the past several years, the Brewer group has studied the reactivity of these intermediates in intramolecular reactions, and have discovered that these cationic heteroallenes can react through a variety of other, mechanistically distinct, pathways to give different classes of nitrogen heterocycles. For example, prior work in the Brewer group revealed that 1-aza-2-azoniaallene salts could react in an intramolecular [4+2] cycloaddition reaction to give protonated azomethine imine salts containing a 1,2,3,4-tetrahydrocinnoline scaffold. Further study of the scope and limitations of this Diels-Alder-like reaction are described herein. These studies primarily focused on how varying the N-aryl ring and alkene substituents affected the reaction. We discovered that in several instances, the metal mediated reaction did not facilitate the cycloaddition very well, so we searched for alternative ways to facilitate the reaction. We discovered that a non-metallic Lewis acid (TMSOTf) provided very clean products with α-chloroazo compounds. I hypothesized that changing the leaving group adjacent to the azo might further improve the reaction. With this in mind, I developed a technique to prepare α-trifluoroacetoxyazo compounds by treating aryl hydrazones with trifluoroacetoxy dimethylsulfonium trifluoroacetate. This technique is compatible with all types of functional groups including nitro aryl compounds, which gave low yields of the corresponding chloroazo derivatives. Importantly, these α-trifluoroacetoxyazo compounds gave even better cycloaddition results when treated with TMSOTf, and this method is more practical, more environmentally friendly, and greener than the metal mediated technique. This process even returned sterically hindered products in high yield, and provide a dearomatized non-protonated azomethine imine salt, which further verified the proposed mechanism of the [4+2] cycloaddition. Azomethine imines are well known to undergo 1,3-dipolar cycloadditions with alkenes. We wondered if the protonated azomethine imine salts generated by the [4+2] cycloaddition could be used in a subsequent base-mediated [3+2] cycloaddition to generate structurally complex tetra- or pentacyclic products. We were pleased to find that the protonated azomethine imines indeed reacted smoothly with a variety of π-system in the presence of triethylamine to give the corresponding cycloadducts in high yields with moderate to high diastereoselectivities. In an attempt to understand the diastereoselectivity of these [3+2] cycloadditions better, I modeled them computationally. 1 3-dipolar cycloadditions azo compound azomethine imine green synthetic methodology heteroallene salts structurally complex molecules Chemistry Medicinal Chemistry and Pharmaceutics
5	Amino Aacohols : stereoselective synthesis and applications in diversity-oriented synthesis Torssell, Staffan January 2005 (has links) <p>This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol.</p><p>The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain.</p><p>The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.</p> Organic chemistry amino alcohol carbenoid carbonyl ylide cross-metathesis diastereoselective 1 3-dipolar cycloaddition sphingosine Organisk kemi Organic chemistry Organisk kemi
6	Synthèse d’analogues carbonés de la Ribavirine pour leurs activités antivirales / Synthesis of carbonated analogs of Ribavirin for their antiviral activities Cosson, Fanny 24 April 2014 (has links) La Ribavirine est un analogue nucléosidique de la guanosine constitué d'un ribose et d'un noyau triazole. Cet antiviral, synthétisé en 1970, possède une activité contre différents virus comme le virus respiratoire syncytial chez les enfants en détresse respiratoire, les virus des hépatites B et E, ainsi que contre certains cancers et leucémies. Elle est surtout connue pour son utilisation dans le traitement de l'hépatite C, en combinaison avec l'Interféron. Cependant, l'efficacité de cette thérapie est limitée à certains génotypes du virus et les effets secondaires résultants sont nombreux. C'est pourquoi il est nécessaire de trouver d'autres analogues actifs contre l'hépatite C et moins toxiques afin d'offrir un traitement aux 170 millions d'individus atteints de cette maladie chronique et pouvant évoluer vers des cirrhoses et des cancers du foie. Par une méthodologie d'alcynylglycosylation médiée à l'indium suivie d'une cycloaddition 1,3 dipolaire, des C-nucléosides analogues de la Ribavirine ont été synthétisés. L'un deux, SRO-91, a montré une activité antivirale comparable à celle de la Ribavirine vis-à-vis de l'ARN polymérase du virus de l'hépatite C. L'objectif de cette thèse est donc de synthétiser d'autres C-nucléosides analogues sur le modèle de SRO-91. Des modifications ont été effectuées autant sur le ribose que sur le noyau triazole. Concernant les transformations du ribose, nous nous sommes intéressés à la position C2', notamment en introduisant une quaternisation avec différents groupements (CH3, CF3, F …) ou bien en désoxygénant cette position. Cette thèse décrit les différentes stratégies explorées pour la synthèse de plusieurs de ces C-nucléosides dont les activités antivirales seront étudiées ultérieurement. / Ribavirin is a nucleosidic analogue of guanosine composed of a ribose and a triazole ring. This antiviral compound, synthesized in 1970, exhibits an activity against a broad-range of viruses such as respiratory syncytial virus in respiratory distress children, hepatitis B and E viruses as well as some cancers and leukemia. It is especially known for its use in hepatitis C treatment in combination with Interferon. However, the efficiency of this therapy is limited to a few genotypes of the virus and leads to numerous side effects. Therefore, finding new efficient and less toxic analogs is necessary to treat the 170 million individuals that are chronically infected and at risk of developing cirrhosis and liver cancer. Thanks to a methodology of indium mediated alcynylglycosylation followed by a 1,3-dipolar cycloaddition, C-nucleosides analogs of Ribavirin have been synthesized. Among them, SRO-91, showed a comparable activity to Ribavirin towards hepatitis C virus ARN polymerase. This thesis' objective is to synthesize other C-nucleosides analogs based on SRO-91 model. Modifications have been made on the triazole ring as well as on the ribose. In regards to the ribose transformations, we have been interested into the C2' position, in particular by introducing a quaternisation with different moieties (CH3, CF3, F …) or by deoxygenating this position. This thesis describes the different strategies explored for the synthesis of some of these C-nucleosides whose antiviral activities will be studied later. Ribavirine C-nucléosides Cycloaddition 1-3 dipolaire Glycosylation Hépatite C Synthèse multi-étapes Ribavirin C-nucleosides 1-3 dipolar cycloaddition Glycosylation Hepatitis C Multi-steps synthesis
7	Amino Aacohols : stereoselective synthesis and applications in diversity-oriented synthesis Torssell, Staffan January 2005 (has links) This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol. The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain. The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity. / QC 20101222 Organic chemistry amino alcohol carbenoid carbonyl ylide cross-metathesis diastereoselective 1 3-dipolar cycloaddition sphingosine Organisk kemi Organic Chemistry Organisk kemi
8	1,3-Dipolare Cycloaddition von N2O an hochreaktive Mehrfachbindungen Plefka, Oliver 20 July 2011 (has links) (PDF) In der vorliegenden Arbeit wird über 1,3-dipolare Cycloadditionen mit Lachgas (N2O) unter milden Reaktionstemperaturen (≈ RT) berichtet. N2O ist ein sehr unreaktives 1,3-dipolares Reagenz. Bisher in der Literatur durchgeführte 1,3-dipolare Cycloadditionen mit N2O benötigten immer sehr drastische und gefährliche Reaktionsbedingungen (bis zu 300°C und 500 atm.). Dabei entstanden nach einer (postulierten) einleitenden 1,3-dipolaren Cycloaddition von N2O an Olefine oder Alkine immer nur stickstofffreie Reaktionsprodukte. Durch den Einsatz von hochreaktiven Cycloalkinen als 1,3-Dipolarophile konnten erstmals 1,3-dipolare Cycloadditionen mit N2O bei deutlich milderen Bedingungen (–25°C bis +60°C) als den bisher bekannten durchgeführt werden. Dabei war es mit Cyclooctin und Cycloocten-5-in erstmals möglich, stabile und vollständig charakterisierbare Reaktionsprodukte zu erhalten, die alle drei Atome des addierten N2O-Moleküls enthalten. Mit 4,5-Didehydro-2,3,6,7-tetrahydro-3,3,6,6-tetramethylthiepin konnte sogar erstmals ein alpha-Diazoketon durch 1,3-dipolare Cycloaddition von N2O erhalten und dieses bei –25°C NMR-spektroskopisch untersucht werden. Diese alpha-Diazoketone entstehen aus der elektrocyclischen Ringöffnung der entsprechenden 1,2,3-Oxadiazole welche aus der Cycloaddition von N2O und dem eingesetzten Cycloalkin stammen. Mit alpha-substituierten Cyclooctinen konnten auch 1,3-dipolare Cycloadditionen mit N2O bei milden Temperaturen durchgeführt werden, um stickstofffreie Reaktionsprodukte zu erhalten. Lachgas N2O 1 3-dipolare Cycloaddition [3+2]-Cycloaddition Cycloalkin Cyclooctin Diazoketon milde moderate Bedingungen nitrous oxide N2O 1 3-dipolar cycloaddition cycloalkyne cyclooctyne mild moderate condition ddc:547 Distickstoffmonoxid Ringspannung
9	Bildungstendenz und Reaktionen von α-Azidoalkoholen Berndt, Christian 24 April 2013 (has links) (PDF) Gegenstand der vorliegenden Arbeit ist die Synthese von α-Azidoalkoholen durch die Reaktion von aliphatischen sowie aromatischen Aldehyden mit Stickstoffwasserstoffsäure. Dabei stellt sich ein Gleichgewicht ein, dessen Lage durch die Ermittlung der Gleichgewichtskonstanten quantitativ bestimmt wird. In jedem Fall besteht die Möglichkeit, den α-Azidoalkohol in der Gleichgewichtsmischung zu charakterisieren und teilweise gelingt die Isolierung der reinen α-Azidoalkohole bei tiefen Temperaturen sowie deren Charakterisierung mittels Tieftemperatur-NMR-Spektroskopie. Die Ausgangsaldehyde für die Synthese der α-Azidoalkohole besitzen elektronenschiebende oder elektronenziehende Substituenten oder sind prochiral oder besitzen funktionelle Gruppe für intramolekulare Reaktionen. Die Titelverbindungen werden mit Cyclooctin im Sinne einer 1,3-dipolaren Cycloaddition abgefangen oder mit Carbonsäurechloriden in die entsprechenden Ester der α-Azidoalkohole überführt. Das nur aus theoretischen Arbeiten bekannte Formylazid wird erstmals aus den α-Azidoalkoholen durch Oxidation hergestellt und in Lösung vollständig charakterisiert. Es werden zudem zahlreiche Alternativsynthesen für Formylazid erfolgreich durchgeführt. α-Azidoalkohole chemische Gleichgewichte nucleophile Addition 1 3-dipolare [2+3]-Cycloaddition Formylazid α-azido alcohols aldehydes hydrazoic acid balance reactions nucleophilic addition alcohols azides 1 3-dipolar cycloaddition esterification oxidation formyl azide ddc:547 Aldehyde Stickstoffwasserstoffsäure Alkohole Azide Triazole Veresterung Oxidation
10	Neue binäre CN-Verbindungen sowie Vorläufersubstanzen von monomerem C3N4 Richter, Sebastian 24 November 2014 (has links) (PDF) Gegenstand dieser Arbeit sind Versuche zur Synthese neuer binärer Kohlenstoffnitride im Allgemeinen und von C3N4-Vorläuferverbindungen im Speziellen. Hierbei werden v. a. die Herstellung und die Eigenschaften organischer Polyazide beschrieben, die aufgrund ihrer Gefährlichkeit durch zahlreiche Folgereaktionen in weniger brisante Moleküle überführt werden mussten. Als Derivatisierungsreaktionen kamen hierbei beispielsweise die 1,3-dipolare Cycloaddition mit Norbornen und Cyclooctin, die STAUDINGER-Reaktion mit verschiedenen Phosphinen sowie die Aza-WITTIG-Reaktion zum Einsatz. Es konnten dabei u. a. zehn Röntgeneinkristallstrukturen erhalten und als Strukturbeweis aufgeführt werden. Zahlreiche hochaufgelöste Massenspektren sowie Elementaranalysen und NMR-Daten bestätigten außerdem alle neu erhaltenen Strukturen. Einen weiteren Schwerpunkt dieser Arbeit stellen Versuche zur Synthese von monomerem C3N4 dar, dessen Herstellung zwar nicht gelang, für dessen Bildung allerdings neue Möglichkeiten ausgehend von verschiedenen Edukten beschrieben werden. Darüber hinaus wurden bereits bekannte Moleküle auf ihre Eignung als C3N4-Vorläufer untersucht, wobei z. B. durch Azid-Addition an Nitrilgruppen unerwartete neue Produkte erhalten werden konnten. Aminale Aza-Wittig-Reaktion Azide Aziridine C3N4 Cyantriazenide Cyclooctatriazole Dehydratisierung 1 3-dipolare Cycloaddition Iminophosphorane 15N-Markierung Nitrile Phosphazide Reduktion Staudinger-Reaktion TCNE Tetrazole Tieftemperatur-NMR-Spektroskopie aminales aza-Wittig-reaction azides aziridines C3N4 cyanotriazenides cyclooctatriazoles dehydration 1 3-dipolar cycloaddition iminophosphoranes 15N-labelling nitriles phosphazides reduction Staudinger-reaction TCNE tetrazoles low temperature NMR spectroscopy ddc:547 Aminale Azide Aziridine Dehydratisierung Iminophosphorane Nitrile Reduktion Staudinger-Reaktion Tetracyanoethylen Tetrazole

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