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1
Pogozhev, Dmitry. "Sequential construction of crystalline heterometallic architectures based on 7-azaindole and dipyrrin ligands." Strasbourg, 2010. http://www.theses.fr/2010STRA6060.
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Les polymères de coordination revêtent un grand intérêt de par leurs applications potentielles dans les domaines de la catalyse ou du stockage de gaz, par exemple. Alors que la majorité des architectures décrites sont homométalliques, l'obtention de leurs analogues hétérométalliques représente un défi synthétique. En effet, une approche «one-pot)), par principe, peut mener à un mélange statistique de composés homo- et hétérométalliques. Afin de résoudre ce problème, une stratégie séquentielle a été mise au point. Elle repose sur l'utilisation de ligands portant des pôles de coordination différenciés. Celte voie a été développée à partir de ligands dérivés du 7-azaindole et de la dipyrrine. Dans une première partie, des dérivés fonctionalisés du 7-azaindole ont été synthétisés et utilisés comme ligands pour la préparation de complexes et de réseaux à base de Cu(II). Dans une deuxième partie, des dérivés de la dipyrrine portant un groupement imidazolyle, pyrazolyle ou pyridyle périphérique ont été préparés ainsi que leurs complexes hétéroleptiques de Cu (II) et Co(III). Ces composés forment par auto-assemblage avec des sels d'argent, : AgX, des architectures hétérométalliques ' mono- et bi-dimensionnelles. L'organisation de ces réseaux est influencée la nature de l'anion X-. Dans une troisème et dernière partie, un ligand comprenant à la fois les noyaux dipyrrine et 7-azaindole a été synthétisé. Ce dernier groupement montre une récurrence d'un motif auto-complémentaire de liaison hydrogène. Ainsi, les complexes obtenus par coordination de la fonction dipyrrine à des métaux divalents tels que Ni(II), Cu(lI) et Zn(lI) forment des réseaux unidimensionnelsCoordination polymers have altracted considerable interest over the past few years owing to their potential application in gas storage or catalysis, for example. While the vast majority of these compounds are homometallic systerns, the synthesis of heterometallic architectures remains challenging. Indeed, a one-pot synthetic approach in principle leads to a statistical mixture of homo- and hetero-metallic assemblies. To circumvent this synthetic issue, a sequential approach has been developed. The lalter relies on the use of ligands bearing differentiated coordination sites hence allowing the stepwise elaboration of heterornetallic architectures. This approach has been explored by ligands based on the 7-azaindole and dipyrrin moieties. Ln a first parI, functionalized 7-azaindole derivatives have been synthesized and employed as ligands for the preparation of Cu(II) discrete complexes and networks. In a second part of the work, novel dipyrrin appended with imidazolyl, pyrazolyl or pyridyl groups have been prepared and used as ligands for the synthesis of heteroleptic Cu(lI) and Co(III) complexes. These species form mono- and bi-dimensional networks upon assembly with sil ver salts, AgX. The solid state arrangement of these species is influenced by the nature of the X- anion. In a third and final parI, a ligand incorporating both a dipyrrin and a 7-azaindole has been conceived and prepared. The lalter shows a recurrent hydrogen bonding motif that leads to the formation of one-dimensional networks upon coordination of, divalent metals such as Ni(II), Zn(lI) and Cu (II) by the dipyrrins
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Saab, Fabienne. "Inhibiteurs de la voie Raf/MEK/ERK : synthèse de composés à structure 4-azaindolique et évaluation de leur efficacité par la mise au point de tests TR-FRET." Phd thesis, Université d'Orléans, 2010. http://tel.archives-ouvertes.fr/tel-00503901.
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Afin de corriger la suractivation de la voie de signalisation Raf/MEK/ERK observée dans 30 % des cancers,nous avons choisi d'inhiber la kinase Raf-1. Les inhibiteurs potentiels de Raf-1 ont été conçus avec un cyclecentral original 4-azaindolique. Pour apporter de la diversité fonctionnelle au niveau des sommets C-2 et C-5lors de la synthèse, nous avons optimisé deux méthodes à partir du synthon 5-méthoxy-4-azaindole-Nphénylsulfonyle.La première est une réaction de lithiation du sommet C-2 suivie de la condensation dedifférents électrophiles et la deuxième est la C-arylation ou N-arylation du sommet C-5 à partir du dérivétriflate en 5 via des réactions de couplage pallado-catalysées de type Suzuki et Buchwald, respectivement.Ces deux méthodes ont permis d'aboutir à 2 séries de composés : une première série fonctionnalisée enposition N-1 et C-5 du noyau 4-azaindole et une deuxième série substituée en position C-5 et C-2.Pour tester les nouveaux inhibiteurs synthétisés et un inhibiteur naturel appelé PEBP, nous avons mis aupoint des tests d'activité in vitro sur l'ensemble de la cascade Raf/MEK/ERK et sur chacune des 3 kinases.Les tests ont été développés avec 2 méthodes de TR-FRET, Lance UltraTM et LanthascreenTM, et ont étévalidés avec des inhibiteurs commerciaux et comparés par rapport à la méthode radioactive PFBA.Au total, 30 produits finaux ont été évalués in vitro sur la kinase Raf-1. Grâce aux plateformes duCancéropôle GO, les produits ont aussi été testés sur 6 lignées de cellules cancéreuses et sur les kinasesdu cycle cellulaire DYRK1A, GSK3 et CDK5. Plusieurs molécules ont montré une activité antitumoraleencourageante de l'ordre du μM et un composé a été identifié comme inhibiteur de Raf-1 avec une valeurd'IC50 de 9,8 μM et une cytotoxicité sélective vis-à-vis des cellules du foie Huh7 (IC50 = 3 μM).
3
Couhert, Audrey. "Conception de ligands mixtes mélatoninergiques et sérotoninergiques à structure azaindolique et furopyridinique." Thesis, Orléans, 2015. http://www.theses.fr/2015ORLE2008/document.
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La mélatonine est une neurohormone sécrétée en période nocturne dans la glande pinéale. Elle régule les rythmes biologiques et influe sur différents processus physiologiques. Son implication ainsi que celle de la sérotonine, un neurotransmetteur, dans certains troubles de l’humeur font des récepteurs associés à ces deux hormones (MT1, MT2 et 5-HT2C respectivement) des cibles innovantes pour le développement de nouveaux antidépresseurs. Dans le cadre de cette thèse, des ligands mixtes mélatoninergiques et sérotoninergiques en série 7-azaindolique ont été synthétisés et testés biologiquement. L’élaboration de dérivés furo[3,2-b]pyridiniques a permis d’évaluer le potentiel biologique de ce squelette original et de mettre au point une nouvelle méthode de synthèse de ce motif. Ces travaux ont également été l’occasion d’étudier l’influence sur l’affinité et l’activité mélatoninergiques de la présence de différents groupements aryles plus ou moins volumineux en position 2 du noyau. Le dernier objectif a consisté dans le développement d’une voie d’accès à des analogues furopyridiniques tricycliques. Le raisonnement méthodologique poursuivi réside dans la mise en place d’une séquence réactionnelle permettant d’accéder aux structures désirées via une procédure courte et efficaceMelatonin is a neurohormone secreted in the pineal gland during dark phases. This regulator of the biological clock is thus involved in several physiological process. Melatonin and serotonin, a neurotransmitter, are involved in some mood disorders, leading to consider associated receptors (MT1, MT2 and 5-HT2C respectively) as innovative targets for the development of new antidepressant.During this PhD, some 7-azaindolic ligands with both melatoninergic and serotoninergic activity were synthesized and tested from a biological point of view.Elaboration of furo[3,2-b]pyridinic derivatives allow us to evaluate the biological potential of this scaffold and to develop a new synthetic pathway to this pattern. This work has been the opportunity to study the influence of bulky aryl groups at C2 position over affinity and activity of these molecules towards melatoninergic receptors.The last aim consisted in developing a new methodology to access tricyclic furopyridinic analogues with a short and efficient chemical sequence
4
Zhou, Qingqing. "Design Synthesis and Biological Evaluation of DYRK1A Inhibitors." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17716.
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DYRK1A is a dual-specificity protein kinase that catalyses not only autophosphorylation on its tyrosine residue but the phosphorylation of serine and threonine residues in its substrates. DYRK1A has been shown to be important for phosphorylation of tau protein and has also been identified as a Down syndrome candidate gene. DYRK1A overexpression has also been found in cancer cells, particularly in glioblastoma, which represents 15% of brain tumours. The increased phosphorylation of sprouty2 mediated by DYRK1A blocks the EGFR degradation as a result of overexpression of EGFR in the cell surface, and the enhanced EGFR signalling eventually leads to tumour survival. On the contrary, DYRK1A inhibition has been found to promote EGFR degradation in glioblastoma cells by triggering the endocytosis and lysosomal degradation, thus reducing the self-renewal ability of tumourigenic cells. Development of small molecule inhibitors of DYRK1A therefore provides attractive treatment strategies. A recently discovered lead compound, DANDY represents one chemotype of the most potent DYRK1A inhibitors. The work in this thesis explores the importance of the 7-azaindole skeleton to DYRK1A inhibition through the systematic modification to structural features of DANDY. The sequential selectivity of promising inhibitors over other off-targets such as DYRK1B, DYRK2 and CLK1, as well as the functional activity against glioblastoma cells has also been explored. Preliminary kinase inhibition assays together with cell viability assays have shown promising trends towards the correlation between DYRK1A inhibition activities and cellular efficacies in vitro. In this thesis, several promising compounds have shown inhibition for DYRK1A with IC50 values being < 50 nM. These compounds have also played effective roles for the in vitro treatment of glioblastoma cell viability assays.
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Kallinen, Annukka. "The Design, Synthesis and Evaluation of Novel CB2 Ligands." Thesis, The University of Sydney, 2019. https://hdl.handle.net/2123/21461.
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The pathophysiology of brain injury and a variety of neurodegenerative diseases involves an inflammation cascade that causes neuronal loss and damage in the central nervous system (CNS) over time. A diagnostic tool that could allow earlier detection and intervention of neuroinflammation is currently missing. Under inflammatory conditions, an increase in the expression of cannabinoid receptor 2 (CB2) is observed in microglia that are the resident macrophages in CNS. Thus, CB2 represents a potential imaging biomarker and a therapeutic target for neuroinflammatory diseases. The aim of this work was to develop specific 18F-radioligands (T1/2 = 109.7 min) targeted at CB2 for the detection of activated microglia in vivo by positron emission tomography (PET). The first compound series consisted of fluorinated benzimidazole 5-sulfones. Several derivatives were found to show low nanomolar CB2 potency and excellent selectivity over CB1 subtype. Selected ligands with high CB2 binding affinity were radiolabelled and isolated with non-decay corrected (ndc) radiochemical yield (rcy) of 2040%, with high radiochemical purity (>95%), molar activity of 200 GBq/mol and good formulation stability. The radioligand candidates were observed to show low brain uptake in healthy rats, as expected in baseline conditions. The second series comprised of fluorinated azaindoles that were found to display restricted structure-activity relationship, with few analogues showing low nanomolar CB2 activity and sufficient subtype selectivity. The first ligand candidate was labelled using Cu-mediated 18F-fluorination with 10% rcy (ndc), high radiochemical purity (>95%) and formulation stability. The radioligand showed rapid uptake in CB2-rich spleen and had promising uptake in healthy rat brain. To summarise, the compounds investigated showed excellent in vitro and promising in vivo properties. As the next step, the CB2-specificity will be studied in greater detail in suitable neuroinflammation models.
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Girard, Anne-Lise. "Hétérocyclisation par carbolithiation intramoléculaire d’alcynes. Applications à la construction de polyhétérocycles aromatiques." Rouen, 2007. http://www.theses.fr/2007ROUES043.
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Une réaction de cyclisation par carbométallion intramoléculaire d’alcynes ou d’alcènes a été appliquée à la synthèse d’hétérocycles binucléaires ([4. 3. 0] et [3. 3. 0]). Ce travail décrit plus particulièrement l’hétérocyclisation de composés aromatiques porteurs d’une chaîne propargylique terminée par un groupe acétal. Cette réaction de carbolithiation permet notamment de transformer des éthers et des amines aromatiques en 3-vinyl benzofuranes ou indoles via une séquence domino cyclisation-élimination. Une étude mécanistique de chaque étape nous a permis de détailler cette séquence réactionnelle grâce à des travaux expérimentaux, menés en parallèle à une étude théorique DFT. Un intermédiaire dihydrobenzofuranique non attendu, porteur d’une double liaison exocyclique E, a été obtenu avec un bon rendement et une sélectivité inédite. Ces résultats permettent de mieux appréhender le « moteur » thermodynamique de la cyclisation et surtout l’origine de la stéréosélectivité de la séquence. Des modifications structurales ont pu être apportées aux systèmes aromatiques de départ afin d’estimer les cibles hétérocycliques susceptibles d’être atteintes. Nous avons ainsi accédé à un squelette azaindole, isostère du noyau indolique présentant un intérêt paharmaceutique, avec de très bons rendements et une bonne stéréosélectivité. Dans le but d’élargir le champ des transformations synthétiques possibles sur l’intermédiaire vinylmétal résultant de la carbométallion intramoléculaire, cette étude a été étendue à d’autres métaux ( en particulier le magnésium). Nous avons également cherché à identifier les fonctions en position propargylique terminale qui sont favorables à l’hétérocyclisation. Dans le cas du magnésium, nous avons montré que la présence d’un motif acétalique acyclique de nos substrats originels est nécessaire pour que la cyclisation puisse avoir lieu, comme pour la carbolithiation. Enfin, nous avons tenté d’étendre le champ d’application via une nouvelle cyclisation par aminométallion intramoléculaire. Un hétérocycle [4. 4. 0] a ainsi été obtenu avec un rendement modesteA ring closing reaction based on the intramolecular carbometallation of alkynes or allenes has been applied to the synthesis of [4. 43. 0] and [3. 3. 0] binuclear heterocycles. The work has been mainly applied to aromatic substrates bearing a propargylic lateral chain ended with an acetal appendage. The carbolithiation transforms aromatic ethers and amines into 3-vinyl-benzofuranes and -indoles via a cyclization-elimination domino sequence. The intimate mechanism of this procedure has been studied in details thanks to a parallel theoritical and experimental investigation. An unexpected dihydrobenzofuran intermediate has been obtained in good yoelds and with an unprecedented E selectivity. These results provide hints on the thermodynamics of the cyclization and on the origin of the selectivities of the overall sequence. Alteractions brought to the aromatic starting material have also given a few clues about possible heterocyclic targets. We have thus been able to access an azaindole skeleton, a pattern highly regarded in pharmacy for its indole-like properties, in high yield and selectivities. In an attempt to extend the scope of the synthetic possibilities opened by the carbometallion applied to the heterocyclization, we have next tried to take advantage of other metals, and in particular magnesium. As in carbolithiation, we have also probed the sensivity of the cyclization to structural alterations on the propargylic substrates. The results show that an open-chain acetal attachment is required for the cyclization to proceed smoothly. Finally, we have tried to further extend the field of applications by studying an intramolecular aminometallion of an alkyne. In one case could a [4. 4. 0] heterocycle be obtained, however in modest yields
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Wu, Qingguo. "Luminescent organic and organometallic compounds based on 7-azaindole, 2,2'-dipyridylamine, 8-hydroxyquinoline and derivatives and their electroluminescent applications." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0010/NQ52866.pdf.
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Bronner, Catherine. "Complexes cyclométallés coordinants pour la construction d'assemblages hétérométalliques." Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/BRONNER_Catherine_2010.pdf.
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L’utilisation de composés moléculaires coordinants et modulables (nature, nombre, différenciation et disposition des sites de coordination) pour la construction séquentielle de matériaux ou d’assemblages moléculaires finis offre de nombreuses possibilités conceptuelles et synthétiques. Les complexes métalliques sont en particulier de très intéressantes briques de construction en raison de la diversité de leurs propriétés physiques ajustables (magnétique, optique, électrochimique). Nous nous sommes intéressés plus particulièrement au cours de ce travail à l’utilisation de fragments cyclométallés permettant d’introduire une propriété de luminescence au sein des complexes. Le premier chapitre traite ainsi de l’utilisation conjointe d’un ligand cyclométallant et des ligands de type dipyrrine pour la formation de complexes de platine, palladium et iridium. Les propriétés photophysiques de ces composés ont été caractérisées et démontrent la luminescence de ces composés. La formation d’assemblages discrets hétérobinucléaires a permis d’étudier une synergie entre les deux centres métalliques. Le second chapitre s’articule autour de ligands ène-dithiolates pour l’obtention de complexes de platine et de palladium. Un nouveau ligand cyclométallant a également été employé dans le but de tendre vers des architectures infinies. Enfin, des ligands pontants de la famille des 7-azaindole ainsi que des 2-thiopyridine ont été mis à profit pour la formation de dimères de platine. L’oxydation de ces composés homobimétalliques et leur fonctionnalisation ont été abordéesThe use of coordinating molecular species with tuneable features (nature, number, differentiation and disposition of the coordination sites) for the step-by-step construction of materials or discrete supramolecular assembly offers many conceptual and synthetic possibilities. Metallic complexes are especially very attractive building blocks because of the diversity of their adjustable physical properties (magnetical, optical, electrochemical). In this work, cyclometallated fragments have particularly being use owing to the potential luminescence of their complexes. The first chapter deals with the use of a cyclometallating ligand and a ligand from the dipyrrin family for the preparation of platinum, palladium and iridium complexes. Their photophysical properties were characterized and have shown that these species are luminescent. The formation of discrete heterobinuclear assemblies has been investigated towards a synergy between the two metallic centres. The second chapter is based on ene-dithiolate ligands to afford platinum and palladium complexes. A new cyclometallating ligand was employed to aim at infinite architectures. Finally, bridging ligands from the 7-azaindole family as well as the 2-thiopyridine were used to form platinum dimmers. The oxidation of these homobimetallic compounds as well as their functionalization has been investigated
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Lefoix, Myriam. "Synthèse de 5-azaindolocarbazoles.Evaluation de leur activité antitumorale." Phd thesis, Université d'Orléans, 2005. http://tel.archives-ouvertes.fr/tel-00148832.
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Le cancer est un problème de santé publique majeur. La recherche en chimiothérapieprogresse, afin de développer de nouveaux composés plus spécifiques, diminuant les effets
secondaires et les phénomènes de résistance. Les indolocarbazoles, molécules naturelles aux
propriétés antitumorales, représentent un outil de choix pour cette thérapie. Les
modifications réalisées sur ce squelette, à savoir le remplacement d'une sous-structure
indolique par un 5-azaindole, ont permis de synthétiser des 5-azaindolocarbazoles.
Une étude approfondie de la réactivité du 5-azaindole a été nécessaire. La fonctionnalisation
des sommets 2 ou 3, réalisée au cours de diverses réactions, autorise la synthèse de composés
plus complexes. Elle a déjà permis d'accéder aux différents 5-azaindolocarbazoles ciblés. Les
activités biologiques, particulièrement intéressantes, sont également rapportées dans le
document.
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Le, Fouler Vincent. "Etude de la réactivité des pyrimidines dans des réactions de Diels-Alder à demande électronique inverse." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAF022.
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La séquence ihDA/rDA est une transformation d’intérêt en synthèse organique en raison de la complexité structurelle à laquelle elle donne accès facilement. A ce jour l’utilisation des pyrimidines dans de telles séquences est encore peu explorée en raison de leur faible réactivité. Dans ce manuscrit sont décrites deux stratégies impliquant des pyrimidines dans une séquence ihDA/rDA pour la synthèse de 4-azaindolines et de 7-azaindazoles. Dans le cadre de la synthèse des 4-azaindolines, les travaux rapportés se concentrent sur la synthèse d’une série d’intermédiaires clés de la synthèse des 4-azaindolines, les N-vinylynamides. Dans le cadre des 7-azaindazoles, une synthèse en 3 à 5 étapes de l’hétérocycle est rapportée utilisant la séquence ihDA/rDA comme étape clé. 30 exemples sont illustrés, ainsi que les résultats faisant suite à un suivi de réactivité, une étude théorique, une montée en échelle et enfin une application concrète de cette nouvelle méthodologie par application sur un composé bioactif connuIhDA/rDA sequence is a very useful transformation for organic synthesis, allowing an easy access to hetero polycyclic structures. Pyridimines reactivity has been under-investigated due to their low reactivity in such sequence. In this manuscript are described two strategies using them in ihDA/rDA sequence for the synthesis of 4-azaindolines and 7-azaindazoles. For the 4-azaindolines, the results reported are focused on the synthesis of key intermediates of the synthesis, N-vinylynamides. For the 7-azaindazoles, a short and efficient synthesis has been developed using the ihDA/rDA sequence as a key step. 30 molecules had been made that way, followed by a reactivity study, a theorical study, a scale-up perspective and finally an application of our new methodology on a bioactive compound
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Coste, Jérôme. "Conception de ligands mixtes mélatoninergiques et sérotoninergiques à structure azaindolique, benzoindolique et indolique." Thesis, Orléans, 2012. http://www.theses.fr/2012ORLE2016.
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La mélatonine est une hormone produite par la glande pinéale durant la nuit. Des études ont montré que des agonistes des récepteurs mélatoninergiques (MT1 et MT2) pouvaient être des antidépresseurs efficaces. Ainsi, a été développée l’agomélatine, un puissant antidépresseur commercialisé par les Laboratoires Servier sous le nom de valdoxan®, agoniste des récepteurs MT1, MT2 et antagoniste du récepteur 5-HT2C. Le travail de cette thèse a eu pour but d’élaborer un successeur à l’agomélatine possédant un profil pharmacologique similaire. Dans une première partie, des ligands à structure 4- et 6-azaindolique ont été synthétisés. Notre premier effort a été de développer la voie de synthèse de ces molécules via la réaction de Fischer, puis, ce travail a débouché sur l’optimisation de cette réaction par l’utilisation des micro-ondes. Par la suite, notre recherche s’est portée sur la synthèse de composés 7-azaindoliques et benzoindiques, ceci découlant d’une étude de la relation structure-activité entre les ligands et les récepteurs MT. Ensuite, ont été synthétisés des analogues à structure indolique ayant une affinité pour les récepteurs MT1 et MT2 connue, sur laquelle nous avons greffé un motif bispyridinique sensé apporté une activité 5- HT2C. Enfin, des ligands indoliques dichlorés ont également été mis au point. L’ensemble de ce travail a permis l’élaboration de quelques composés dont le profil est intéressant et qui sont toujours à l’étudeMelatonin is a hormone produced by the pineal gland during the night. Some studies have shown that agonists of melatoninergic receptors (MT1 and MT2) could be efficient antidepressants. Few years ago, Agomelatine, an agonist of MT1, MT2 receptors and antagonist of 5-HT2C receptor, was developed by Les Laboratoires Servier, The goal of this thesis was to design a molecule with a similar pharmacological profile. First, some 4- and 6-azaindolic ligands were synthesised. We work around the development of the method to synthesised this molecules via the Fischer cyclisation and improved it by micro-ondes using. Second, following structure-activity studies with MT receptors, we have synthesised 7-azaindolics and benzoindolics compounds. Third, some indolics analogs presenting a good MT1 and MT2 affinity were coupled with a bispyridinic entity to enhance an 5-HT2C activity. Finally, dichloroindolics ligands were synthesised. All this work allows the synthesis of interesting ligands. Some of these molecules are still on study
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DEKHANE, MOULOUD. "Etude d'agents agissant sur le systeme nerveux central : synthese par une une voie originale de 6-azaindole-5-carboxylates et de bata-carboline-3-carboxylates, ligands du recepteur des benzodiazepines. synthese de beta-carbolines quaternisees, agents inhibiteurs de l'acetylcholinesterase." Paris 11, 1994. http://www.theses.fr/1994PA112080.
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Les travaux de ce memoire sont presentes en deux parties distinctes et ont comme theme commun la synthese de molecules heterocycliques interagissant avec le systeme nerveux central. Dans la premiere partie, une nouvelle voie de synthese rapide et convergente de 6-azaindoles monosubstitues en c-5 et disubstitues en c-3, c-5 et c-4, c-5 est decrite a partir d'un pyrrole-2-carboxaldehyde et d'un beta-acetal (ou beta-cetal)-alpha-aminoester. Cette methodologie a ete appliquee a l'elaboration de beta-carbolines substituees en c-3 et c-4 a partir de l'indole-2-carboxaldehyde et du meme aminoacetal ou aminocetal. Dans la deuxieme partie, nous presentons la synthese de differentes molecules a squelette beta-carbolinium et 1,2,3,4-tetrahydro-beta-carbolinium mono et polysubstituees. Une etude des relations structure-activite de ces produits, en tant qu'inhibiteurs de l'acetylcholinesterase, est detaillee. Les affinites in vitro de ces beta-carbolines quaternarisees pour les recepteurs des benzodiazepines, muscariniques et de la phencyclidine sont egalement presentes
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Donati, Ludovic. "L' unité ortho-bromobenzamide : étude de la réactivité en couplage organopalladié et application à la synthèse de pyridopyrroloisoquinolones et de phénanthridinones à potentialité thérapeutique." Paris 5, 2010. http://www.theses.fr/2010PA05P636.
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Ce projet se place dans le cadre de la préparation de nouveaux composés antitumoraux, analogues de la fagaronine et de la nitidine, alcaloïdes naturels inhibiteurs de la topoisomérase I. Les nouvelles structures envisagées sont de type pyridopyrroloisoquinolones et pyridopyrroloquinolones. Les stratégies de synthèse mises en oeuvre ont conduit à la formation de nouveaux produits possédant une structure tétracyclique ou tricyclique inattendues. Afin de comprendre la réactivité du motif orthobromobenzamide en pallado-catalyse, la formation des dérivés tricycliques a fait l'objet d'une étude mécanistique (RMN, Masse et DFT). Pour la première fois une corrélation directe entre la base carbonatée et le solvant a été observée. Les résultats de cette étude ont permis de proposer un cycle catalytique faisant intervenir une espèce Pd(IV). Ce travail a également conduit à la préparation d'une petite chimiothèque d'une trentaine de composésTopoisomerase I constitutes a validated target for the research of new anticancer agents. Two new series of aza-analogues of natural benzophenanthridine alkaloids nitidine and fagaronine were envisaged: pyridopyrroloisoquinolones and pyridopyrroloquinolones. During the synthesis of theses compounds, new tricyclic and tetracyclic heterocycles were unexpectidly obtained. Mechanistical investigations (NMR, mass and DFT) were carried out to understand the formation of the tricyclic compounds starting from orthobromobenzamide unit. The results of this study permitted to present a catalytic cycle including the passage through a transient Pd(IV) species. A small library of thirty compounds has been prepared
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Hodgkinson, Roy. "Synthesis of indoles and azaindoles via copper/palladium catalysed tandem C-N bond coupling." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504479.
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Rost, Ulrike. "Organisation and Recognition of Artificial Transmembrane Peptides." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7CA6-D.
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Mahiout, Zahia. "Synthèse de 5- et 6-azaindoles, de stéroïdes et de composés divalents adénine-stéroïdes : évaluation de l’effet modulateur vis-à-vis de la glycoprotéine P." Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10172.
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La glycoprotéine P ou Pgp est une protéine de transport transmembranaire qui a pour rôle principal d'évacuer hors des cellules les xénobiotiques et les toxines. Elle agit comme une pompe à efflux et est surexprimée par certaines cellules cancéreuses. Ainsi, via ce mécanisme, les cellules tumorales peuvent devenir résistantes aux antitumoraux et conduire à l'échec des traitements lors de la chimiothérapie anticancéreuse. Aussi, la modulation de l'activité de cette protéine peut être un des moyens permettant l'amélioration des traitements anticancéreux. La Pgp possède plusieurs sites de fixation de substrats dont deux sont relativement proches spatialement : un site à stéroïdes et un site à ATP permettant d'hydrolyser l'ATP, source d'énergie nécessaire au fonctionnement de la Pgp. Notre objectif a été de synthétiser des modulateurs bivalents stéroïdes/bras/nucléosides. Pour cela, nous avons dans un premier temps préparé des analogues de bases puriques et plus particulièrement des didéazapurines, les 5- et 6-azaindoles et les trioxopyrrolopyridines correspondant puis effectué la glycosylation de ces derniers. Dans un second temps, des modulateurs stéroïdiens ont été synthétisés : plusieurs ont montré une bonne activité modulatrice de la Pgp. Enfin, des bras polyéthylènes glycols de longueurs variables ont été reliés à l'adénine pour être ensuite fixés aux stéroïdes via une fonction amideP-glycoprotein Pgp is a transmembrane transporter protein that protects cells from potentially toxic exogenous compounds. This protein acts as a molecular pump and is overexpressed in cancer cells. So via that mechanism, tumor cells exhibit intrinsic or acquired cross-resistance to diverse chemotherapeutic agents, resulting in the failure of chemotherapy for some cancers. The modulation of the efflux activity of that protein can be one of the mean that could increase anticancer treatments efficiency. Pgp has different substrates sites, two of which are spatially close : the steroid site and the ATP site, the latter is in charge of ATP hydrolysis which give the required energy for the Pgp efflux activity. Our goal was to synthesize bivalent modulators steroids/linker/nucleosides. First we have obtained purine bases analogues and particularly didéazapurines such as 5- and 6-azaindoles and the corresponding trioxopyrrolopyridines, then we have carried out the glycosylation of those compounds. Then, steroids modulators have been synthesized : some of them have shown a good modulation activity toward Pgp. Finally, polyethylene glycols chains with different length have been grafted on adenine so that they could be attached to the steroids via an amide function
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DOISY, XAVIER. "Synthese de derives de cinq-carboxy-six-azaindoles, une nouvelle classe de ligands du recepteur central des benzodiazepines." Paris 11, 1990. http://www.theses.fr/1990PA112180.
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L'objectif de cette these a ete de synthetiser des composes heterocycliques actifs sur le recepteur des benzodiazepines en utilisant comme vecteur le noyau six-aza-indole, suppose etre le pharmacophore primaire du squelette beta-carboline, ligand de ce meme recepteur. Dans la premiere partie, la synthese et l'etude in vitro d'hybrides de six-azaindole et de benzodiazepine ont ete realisees. Ce travail a permis de completer des etudes de relation structure-activite entreprises sur les molecules hybrides de beta-carbolines et de benzodiazepines, nouvelle classe de ligands du recepteur des benzodiazepines. Dans la seconde partie, des substitutions sur les positions un, deux et trois du noyau six-azaindole ont ete effectuees. Les differents produits synthetises ont ete testes in vitro, et le profil pharmacologique de l'un d'eux, analogue du zk quatre vingt onze mille neuf cent vingt six, a ete determine par test electrophysiologique sur oocyte de xenope. Il a de plus ete experimente sur souris swiss pour l'evitement passif avec apprentissage
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Livecchi, Marion. "Synthèse pallado-catalysée de 5-azaindoles et évaluation de leur activité inhibitrice sur les protéines kinases CK2 et Pim-1." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P616.
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L’inhibition de protéines kinases constitue une voie pleine de promesses pour la découverte de nouvelles thérapies ciblées contre le cancer. En 2003, le criblage de la chimiothèque de l’Institut Curie/CNRS a permis de mettre en évidence une famille de composés actifs sur deux de ces enzymes : CK2 et Pim-1. L’objectif de cette thèse était de synthétiser des analogues des « hits » de la chimiothèque possédant le squelette 5-azaindole afin d’en améliorer les propriétés biologiques. La préparation de tels composés étant peu décrite dans la littérature, trois voies de synthèse flexibles et efficaces ont été développées. L’élaboration de 5-azaindoles diarylés symétriques a tout d’abord été mise au point par hétéroannélation pallado-catalysée à partir de dérivés de la 4-aminopyridine. Les composés monosubstitués en position 2 ont ensuite été obtenus par réaction domino sila-Sonogashira/cyclisation 5-endo. Enfin, un procédé one-pot couplage de Sonogashira/aminopalladation/élimination réductrice a permis d’accéder aux molécules diarylées non symétriques avec une régiosélectivité contrôlée. L’application de ces méthodologies a conduit à la préparation de 70 composés fonctionnalisés dont la cytotoxicité et l’activité inhibitrice sur CK2 ont été évaluées. Une étude structure-activité a été réalisée et les fragments d’intérêt que doit posséder une molécule de type 5-azaindole pour inhiber efficacement la kinase ont ainsi été identifiésProtein kinases represent promising targets for anti-cancer drug design. In 2003, inhibitors of two of these enzymes, CK2 and Pim-1, were identified by the screening of the Curie Institute/CNRS small-molecule library. The aim of this thesis was to synthesize derivatives of these hits with a 5-azaindole scaffold in order to optimize their biological activity. As the synthesis of such molecules was not reported in the literature, efficient and flexible procedures were developed to access to these structures. Diarylated symmetrical 5-azaindoles were thus prepared by palladium-catalyzed heteroannulation from 4-aminopyridines derivatives. The methodology was subsequently extended to silylalkynes and led to monoarylated products through domino sila-Sonogashira/5-endo cyclization. Finally, a one-pot Sonogashira coupling/aminopalladation/reductive elimination afforded unsymmetrical compounds with a total control of the regioselectivity. Using these methodologies, 70 functionalized molecules were easily prepared. Their cytotoxicity and biological activity as CK2 inhibitors were then evaluated. A structure-activity relationship study was performed, which led to the identification of two key structural elements for the CK2 inhibitory potency of 5-azaindoles
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Drießen, Daniel [Verfasser], Thomas J. J. [Gutachter] Müller, and Jörg [Gutachter] Pietruszka. "Diversitätsorientierte Synthese neuer 7-Azaindol-Derivate gegen Therapie-resistente Tumore und Infektionen / Daniel Drießen ; Gutachter: Thomas J.J. Müller, Jörg Pietruszka." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1212238699/34.
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Laot, Yann. "Nouvelles applications de la chimie radicalaire des xanthates à la synthèse d'hétérocycles azotés." Phd thesis, Ecole Polytechnique X, 2011. http://pastel.archives-ouvertes.fr/pastel-00567807.
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Ce manuscrit présente les travaux de thèse effectués sous la direction du Professeur Samir Z. Zard dans le laboratoire de recherche DCSO à l'École Polytechnique de Septembre 2006 à Juillet 2009. Il traite de nouvelles applications de la chimie radicalaire des xanthates à la synthèse d'hétérocycles aromatiques azotés, plus particulièrement les oxindoles, les azaindolines, les dihydropyrrolopyrimidines, les dihydropyrrolopyrimidinones et les dihydroimidazopyrimidinones. Parmi les résultats présentés, deux revêtent une importance particulière : Dans un premier temps, nous avons généralisé la réaction de cyclisation radicalaire sur azote aromatique, initialement découverte au laboratoire sur les pyridines, à d'autres familles d'hétérocycles (pentachloropyridine et pyrimidine). Cette méthode nous a permis d'accéder à des noyaux aromatiques peu ou pas décrits dans la littérature, comme les dihydroimidazopyrimidinones. Dans un second temps, nous avons mis en évidence, lors de la synthèse de fluoroazaindolines, la rupture homolytique d'une liaison carbone-fluor dans des conditions « douces ». A notre connaissance, une telle rupture est extrêmement rare.
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Bock, Xavier. "Développement de nouvelles réactions multicomposants pour la synthèse de polyhétérocycles et applications à la synthèse de dérivés de la famille des pyrrolo[3,4-c]carbazoles." Paris 11, 2007. http://www.theses.fr/2007PA112347.
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Le projet scientifique a consisté à développer de nouvelles réactions multicomposants (MCR) pour la synthèse de polyhétérocycles et à les orienter vers la synthèse de dérivés de la famille des pyrrolo[3,4-c]carbazoles. Pour cela, nous avons mis en valeur la synthèse à trois composants de 5-aminooxazoles développée par le laboratoire. L'utilisation de cette plate-forme 5-aminooxazole, en particulier son caractère diénique, a permis d'étendre considérablement le champ de cette nouvelle MCR. Ainsi, l'introduction de diénophiles a permis de réaliser des réactions de cyclo-addition. La variation de la nature du diénophile ainsi que sa localisation au niveau de l'oxazole a conduit à la synthèse de divers polyhétérocycles hautement fonctionnalisés : 5-hydroxy-6-aza-indolines, isoindolinones et pyrrolopyridinones. D'autre part, à partir des isoindolinones et des pyrrolopyridinones, des réactions de post-fonctionnalisations ont été développées permettant ainsi d'accéder rapidement à deux autres familles d'hétérocycles : les bi-pyrrolo[3,4-a],[3,4-c]carbazoles et les pyrrolo[3,4-c]-β-carbolinonesThe scientific project consisted in developing new multicomponent reactions for the synthesis of polyheterocyles and in applying them to the synthesis of derivatives of pyrrolo[3,4-c]carbazoles' family. The planned strategy to synthesise these compounds involved the use of a three component reaction developed in the laboratory and leading to 5-aminooxazoles. The use of the 5-aminooxazole as a chemical plat-form, in particular its ability to reacts with dienophile to give a [2+4] cycloadduct, allowed us to enlarge the scope of this MCR. In fact, the introduction of dienophiles into the reaction media has led to the synthesis of various poyheterocycles: 5-hydroxy-6-aza-indolines, isoindolinones and pyrrolopyridinones. In addition, from isoindolinones and pyrrolopyridinones, post-functionalization reactions were developed to synthesise two other family of heterocycles: bi-pyrrolo[3,4-a],[3,4-c]carbazoles and pyrrolo[3,4-c]-β carbolinones
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Frischmuth, Annette Dorothee Sophie [Verfasser], and Paul [Akademischer Betreuer] Knochel. "New preparation of functionalized indoles and azaindoles via an intramolecular copper-mediated carbomagnesiation of ynamides,regioselective in situ trapping metalation of arenes and heteroarenes with TMPLi in the presence of metal salts and synthesis of SF5-substituted aromatics and heterocycles / Annette Dorothee Sophie Frischmuth. Betreuer: Paul Knochel." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1110749678/34.
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Yang, Chan-Yi, and 楊正義. "Proton-Transfer Spectroscopy of 7-Azaindole Derivatives." Thesis, 2000. http://ndltd.ncl.edu.tw/handle/66387004189824275819.
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碩士國立中正大學
化學研究所
88
Self-dimerization of 7-azaindole (7AI) has long been recognized for undergoing the excited-state double proton transfer resulting in a large Stokes shifted emission. Drastically different crystal structures between 7AI and 3-Iodo-7-azaindole (3I7AI) have been explored, in which 7AI reveals an unusual hydrogen-bonded tetramer. Whereas 3I7AI in a single crystal exhibits solely the intact doubly hydrogen-bonded dimeric form in which excited-state double proton transfer (ESDPT) takes place with a negligibly small energy barrier. The results provide a prototype to investigate the intrinsic ESDPT in a single crystal environment where the structural information is well documented. In another approach, ground-state therodynamics and excited-state amine/imine tautomerism in 7-azaindoline (7AZD) mediated by the hydrogen bonding formation have been studied by means of absorption and emission spectroscopies. Proton-transfer isomers of 7AZD have been identified through syntheses and spectral characterization of various 7AZD methyl derivatives. Further supporting the previously proposed catalytic-versus-noncatalytic model for the ESDPT reaction.
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Tu, Ting-Hsun, and 杜庭熏. "The Excited State Properties of 6-Azaindole." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/18026707138671661424.
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碩士國立臺灣大學
化學研究所
103
In 1969, Taylor discovered the hydrogen-bond dimer of 7-azaindole and its associated excited-state double proton transfer reaction. We discover that 6-azaindole in nonpolar solvent (e.g. cyclohexane) would self-assemble cyclic hydrogen-bonded trimer. The steric hindrance prohibits simultaneous dual N(1)-H---N(6) H-bonded dimer formation. Instead, self-assembly via N(1)-H---N(6) H-bond takes place in non-polar solvents, forming the H-bonded trimer with an association constant of 6.4 ×106 M-2 in cyclohexane. When UV excitation (310 nm) the H-bonded trimer, it would produce normal emission at 325 nm and undergo ESTPT to result in a tautomer emission at 435 nm .Computational approach further affirms the cyclic H-bond trimer formation and its energetically favorable ESTPT reaction. Otherwise, we also study the properties and photophysical characteristics of 6-azaindole in water and ethanol. In ethanol, 6-azaindole would proceed solvent reorganization to form 1:3 cyclic structure and couple intrinsic proton transfer in the excited state which like the property of 7-hydroxyquinoline in ethanol. In water, the pKa of 6-azaindole protonated form is drastically increased from 8.0 (ground state) to 14.37 in the excited state. When the pH is greater than 10, neutral (normal) is the dominant form in the ground state which has distinct properties of excited state. Following we take two different pH as example. Firstly, at pH = 10.9, 6-azaindole can form the 1:3 cyclic structure through solvent reorganization then proceed excited state proton transfer. The pKa* of the 6-azaindole protonated form is greater than this pH so the cationic emission can also be observed. Secondly, at pH = 12.7, 6-azaindole can undergo proton transfer to form the tautomer as well. In this pH is still smaller than the pKa* of 6-azaindole protonated form so cation would also be produced. Besides, the pKa* (~11.16) of the 6-azaindole tautomer protonated form is smaller than the environment. Therefore, the N1-H may dissociate and end up with the tautomer form after a redistribution of the electron density. This phenomenon can be considered as two-step proton-transfer mechanism. The cationic form is just an intermediate specie in the tautomerization process.
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Leboho, Tlabo Caiphus. "Novel syntheses of 5- and 7- azaindole derivatives." Thesis, 2014.
Find full textAbstract:
This thesis describes the application of the Sonogashira coupling reaction to access a variety of
5-and 7-azaindoles derivatives. The background chapter paints a picture about the importance of
indole-containing compounds and azaindole-containing compounds. In this first chapter,
discovery, synthesis, properties and reactivity of indole and azaindoles were explained.
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Yu, Wei-Sheng, and 游偉盛. "Ground-State Reverse Double Proton Transfer of 7-Azaindole." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/69505373917222185085.
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碩士國立中正大學
化學研究所
87
Dynamics of the ground-state reverse proton transfer in 7-azaindole (7AI(N)) have been investigated by two-step laser-induced fluorescence (TSLIF) in various nonpolar solvents. Comprehensive analyses reveal a previously unrecognized finite rise kinetics for the long-lived transient species. Furthermore, the time-dependent spectral evolution indicates that the TSLIF spectrum obtained at the rise component is different from that of the decay component, while both spectra are red shifted relative to the prompt tautomer emission. The results lead us to propose that the transient species originated from the monomer of the 7AI proton-transfer tautomer (7AI(T)) produced by a minor dissociation channel (~4%) of the excited 7AI(T) dimer, which subsequently undergoes a slow reverse proton transfer via the formation of a 7AI(T)/7AI(N) hydrogen-bonded complex. This proposed mechanism rationalizes the recent thermal lensihg experiment which concluded that the 7AI(T) dimer is only 0.97 kcal/mol higher in energy than the 7AI(N) dimer, while theoretical approaches, in contrast, predict an energy different of >20 kcal/mol.
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林勇國. "Excited-State Double-Proton Transfer of 7-Azaindole Hydrogen-Bonded Complexes." Thesis, 1997. http://ndltd.ncl.edu.tw/handle/84031122721995721599.
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碩士輔仁大學
化學學系
85
My thesis can be divided into two parties: The first, we study the photophysical phenomena of 7-azaindole and different kinds of phosphoric ester. When we excited the complexes of 7-azaindole and short alkane chain of phosphoric ester, we can get the tautomer form emission. When the concentration of phosphoric ester were increase to 3*10-4M, we can observe a blue shift of F2 band emission. On the other hand; in the complexes of 7-azaindole and long alkane chain phosphoric ester system, we can not get the blue shift of the F2 band. We think the blue shift is due to the hydrophobic property of long alkane chain, which stop the getting closer of the other ester. As a result, the local polarity around the complex does not favorite to the existence of ion pair species. The other, we study of the photophysical phenomena the 7-azaindole in the AOT reverse micelles and it'sheavy atom effect. By the UV-Vis spectroscopy and fluorescence spectroscopy we can sure the 7-azaindole get into the reverse micelles. The fluorescence probe was sure in three regions: the core of reverse micelles, ester group region and hydropliobic group region. We can estimate the concentration of the probe by our equation. In the reverse micelles tl complexes of 7-azaindole and acetic acid were distribu the ester group region and hydrophobia region. When water and methanoi in the reverse micelle, location of 7-Azaindole were be in core of reverse micelle. When much more water, the range of water pool will be gettii larger. At final, all of the 7-azaindole were in the center water pool, not in the range of bounding water.
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WU, CHENG-XIANG, and 吳澄翔. "The Azaindole Framework in the Optical Benchmark Toward Design of Bioimage Probes." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/5j2p5a.
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碩士輔仁大學
化學系
106
In vivo, water plays an important catalytic role and also affects the dynamic structural changes of proteins. Understanding the dynamic distribution of water molecules in water-coupled proteins helps to understand the structural changes and functional functions of proteins. Scientists have developed techniques for fluorescent probe spectroscopy to detect protein structures by detecting the spectral fingerprints of hydrated fluorescent molecules. The micro-water environment is related to structural dynamics. Currently, 2,6-diazatryptophan ( (2,6-aza)Trp ) and 2,7-diazatryptophan ((2,7-aza) ) Trp) is the most novel tryptophan derivative probe, which can be docked to the protein tryptophan site by genetic engineering techniques to detect a specific site in the protein, that is beneficial to water-catalyzed proton transfer isomerization. Multiple emission spectra are generated to facilitate direct sensing of the aqueous environment at a specific site in the protein. In this study, we target on the chromophore components of azatryptophans, azaindoles, as research objects. We improved classical molecular dynamics (MD), developed steered molecular dynamics (SMD), umbrella Sampling MD (US) and the potential of mean (PMF) to simulate the water cage reorganization energy for 2,6-diazaindole ( (2,6-aza)Ind ) and 2,7-diazaindole ( 2,7-aza ) Ind) in the explicit water solvent cluster. Then we captured the structures which include water chain, facilitates proton transfer, and part of the water cage molecules form the MD simulation. By Quantum mechanism calculation, we analyzed and evaluated the photophysical and photochemical properties of environmental water molecules for (2,6-aza) Ind) and (2,7-aza) Ind. Throughout the combination of theory and experimental spectroscopy, we would understand the operation mechanism of such fluorescent probes and facilitate the development of fluorescent probes in the future. In molecular dynamics (MD) simulations, we found that in the disordered environmental water clusters and nitrogen protons of both water-coupled (2,6-aza) Ind) and (2,7-aza)Ind could perturb the water cages to make reorganization energy significantly difference. The reorganization energies were estimated by the Eyring equation, which is reflected in the same order of nanosecond of the experimental resolution spectrum lifetime. In this way, the water cage reorganization energy of azainoles might probably be affected by the biological micro-water environment in the protein, and cause different reorganization energies in the life cycle. In addition, we found that the (2,6-aza) Ind and (2,7-aza) Ind effective water molecular proton transfer chains are dynamically distributed. In quantum calculation, we found that water cage molecules coould reduce the activation barrier and promote the proton transfer reaction. Moreover, we also verified the steady state of the ground state and excited azaindole isomers and their corresponding proton transfer barriers. We found that the potential difference between N(2)H and N(1)H isomers of (2,6-aza)Ind and (2,7-aza)Ind in the ground state is about 2 kcal mol-1. According the thermal equilibrium, (2,6-aza)Ind and (2,7-aza)Ind can form the N(2)H isomer in the ground state. And the fluorescence calculation wavelengths of the N(1)H and N(2)H structures of (2,6-aza)Ind) are very close (362 nm / 369 nm). Therefore, it is inferred that the emission spectra of the N(1)H and N(2)H isomers of (2,6-aza)Ind may overlap. In the prediction of the reaction pathway, we found that (2,7-aza)Ind predicts the proton tunneling effect when pulling N(7) and the proton bond distance of water molecules as the reaction pathway. Compared with the push N(1) -H bond distance as the reaction pathway, the resulting activation energy barrier is relatively small 3-5 kcal mol-1, and the reaction time calculated value is relatively close to the experimental spectral value. Therefore, in the excited state proton transfer reaction of (2,7-aza)Ind, the tunneling transfer between the N(7) site and the proton of water molecules could play an important role.
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Zhao, Shu-Bin. "REACTIVITY AND LUMINESCENCE STUDY OF PLATINUM AND COPPER COMPLEXES OF 7-AZAINDOLE DERIVATIVES." Thesis, 2008. http://hdl.handle.net/1974/1212.
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The objective of this thesis is to explore new reactivities and to improve luminescent properties of 7-azaindole-containing metal complexes. Selectivity for the activation of toluene and ethyl benzene has been investigated with two cationic Pt(II)(N,N-L) complexes, where N,N-L = 1,2-bis(1-N-7-azaindolyl)benzene (BAB) or bis(1-N-7-azaindolyl)methane (BAM). A high regioselectivity toward toluene and ethyl benzene benzylic C-H activation and a distinct diastereoselectivity for ethyl benzene benzylic C-H activation are demonstrated. Detailed mechanistic studies have been performed, leading to the establishment of both the intermediacy of the η3-benzylic Pt(II) complexes in the reactions and the ligand steric impacts as origins for the distinct diastereoselectivity. A PtMe2 complex of 1-N-(pyridin-2-yl)-7-azaindole (NPA) has been synthesized and found to undergo facile transformation at ambient temperature, resulting in the quantitive formation of a neutral Pt4 molecular square. The mechanism of the transformation process has been examined, establishing a distinct intramolecular C-H driven self-assembly process. The geometrical impacts of the BAB and BAM ligands on the structure and stability of their fac-Pt(IV)Me3 complexes has been investigated. The BAB ligand is more effective than the BAM ligand in stabilizing the five-coordinate Pt(IV)Me3 complexes. With the BAB ligand, a five-coordinate fac-Pt(IV)Me3 complex is obtained; with the BAM ligand, two six-coordinate fac-Pt(IV)Me3 complexes are obtained. In solution, the methyl groups in the BAB complex exchange slowly, but those in the BAM complexes exchange rapidly.
Several new 7-azaindolyl derivative ligands via either modifying or altering the BAM and BAB bridging groups have been developed. The syntheses, structures and reactivities of their Pt(II) complexes have been examined, leading to the finding of an unconventional C-Sn oxidative addition reaction. The modification of the NPA ligand via the incorporation of a triarylboron group has been carried out. Several novel Pt(II) and Cu(I) complexes have been synthesized and studied. A Cu(I) complex is found to display exceptionally bright ambient temperature phosphorescence. A series of dinuclear Cu(I) compounds of the 1,2,3,4-tetra(1-N-7-azaindolyl)benzene (TTAB) ligand have been synthesized and examined. The close contacts between the TTAB bridging phenyl ring and the Cu(I) centers are present in the complexes.Thesis (Ph.D, Chemistry) -- Queen's University, 2008-05-21 18:10:58.628
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Wu, Yu-Sin, and 吳毓心. "Water-Catalyzed Excited-State Proton Transfer Reactions in 7-Azaindole and Its Analogues." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/25189276906374297606.
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碩士國立臺灣大學
化學研究所
102
The mechanism of water-catalyzed excited-state proton transfer (ESPT) reaction for 7-azaindole (7AI) has long been investigated, but there are some controversial viewpoints. Recently, owing to the superiority of sensing biowaters in proteins by a 7AI analogue, 2,7-diazatryptophan, it is timely to reinvestigate water-catalyzed ESPT in 7AI and its analogues in an attempt to unify the mechanism. Herein, a series of 7AI analogues and their methylated derivatives were synthesized to carry out a systematic study on pKa, pKa* and the associated fluorescence spectroscopy and dynamics. The results conclude that all 7AI derivatives undergo water catalyzed ESPT in neutral water. However, for those derivatives with electron-donating substituent (including –H) at C(3), following water catalyzed ESPT to form an excited N(7)-H proton-transfer tautomer, T*, rapid protonation takes place to generate an excited cationic (TC*) species that subsequently undergoes a fast deactivation to the N(1)-H normal species in the ground state. Conversely, protonation in T* is prohibited for those derivatives with an electron-withdrawing groups at the C(2) or C(3), or C(2) atom replaced by an electron-withdrawing nitrogen atom (N(2) in e.g., 2,7-diazatryptophan), giving a prominent green T* emission. Additional support is given by the synthesis of the corresponding N(7)-CH3 tautomer species, for which pKa* of the cationic form, i.e., the N(7)-CH3N(1)-H+ species, is measured to be much greater than 7.0 for those with electron-donating C(3) substituents, whereas it is lower than 7.0 upon anchoring electron-withdrawing groups. For 7AI the previously missing T* emission is clearly resolved with peak wavelength at 530 nm in the pH interval of 13.0-14.5.
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LIN, SSU-YU, and 林思妤. "Synthesis of 7-Azaindole-based HDAC Inhibitors as a Potential Therapy for Alzheimers Disease." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/67f8ct.
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Cash, Michael T. "Kinetic isotope effect in the [beta]-subunit mechanism of tryptophan synthase ; excited state tautomerization of azaindole." 2003. http://purl.galileo.usg.edu/uga%5Fetd/cash%5Fmichael%5Ft%5F200308%5Fms.
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Hsieh, Wan-Ting, and 謝宛廷. "Excited-State Double Proton Transfer: the Concerted (Homodimer) versus Stepwise (Heterodimer) Reaction on the 7-Azaindole Analogues." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/75828365330468029586.
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碩士國立臺灣大學
化學研究所
95
A four fused-ring system 11-propyl-6H-indolo[2,3-b]quinoline (6HIQ) is strategically designed and synthesized; it possesses a central moiety of 7-azaindole (7AI) and undergoes excited-state double proton transfer (ESDPT). Despite the concerted ESDPT in the 6HIQ dimer, femtosecond dynamics unveils a stepwise ESDPT process in the 6HIQ/7AI heterodimer complex, in which 6HIQ delivers the pyrrolyl proton to 7AI in less than 150 fs, followed by the transfer of pyrrolyl proton from 7AI to the pyridinyl nitrogen of 6HIQ in ~1.5 ± 0.3 ps.
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Hsieh, Wan-Ting. "Excited-State Double Proton Transfer: the Concerted (Homodimer) versus Stepwise (Heterodimer) Reaction on the 7-Azaindole Analogues." 2007. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2506200711241400.
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Pires, Marina Joana Dias. "Development of novel synthetic strategies towards azaindoles as promising COXs inhibitors." Doctoral thesis, 2017. http://hdl.handle.net/10362/28059.
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Hwang, Wen-Chi, and 黃文基. "The Studing of Excited-State Double Proton Transfer in The Complexes of 7-Azaindole and .alpha.-Carboline With Various Kinds of Acid." Thesis, 1994. http://ndltd.ncl.edu.tw/handle/42896945408286871355.
Full textAbstract:
碩士輔仁大學
化學學系
82
The acid catalyzed excited state double proton transfer (ESDPT) in 7-Azaindole and .alpha.-Carboline has been studied. In carboxylic acid and phosphoric acid,the formation of a 1:1 cyclic hydrogen bonding acid/7-Azaindole complex was observed with a remarkable large association constant of >10000(1/M) in contrast to alcohol catalyzed ESDPT,in which the solw ESDPT dynamics involve a large amplitude of solvent reorganization, the rate of acid catalyzed ESDPT >>the decay rate(1000000000 1/S) of normal emission,resulting in a unique tautomer emission. The high efficiency acid catalyzed ESDPT in 7-Azaindole as a suitable acid derivatives probe in hydrophobic enviroment such as in cell membrane. The structure and heat of formation of various 7-Azaindole (7-AI) hydrogen bonded complexes have been studied on the basis of the ab initio(6-31G.castrsk.).The enthalpy .DELTA.H of the dimerization reactions was estimated to be -14.2 Kcal/mol, -11.3 Kcal/mol,-9.2 Kcal/mol for 1:1 acetic acid/7AI,7AI/7AI and methanol/7AI complexes,respectively. These values are qualitatively in agreement with the experiment results of -11, -9.5 and -6.3 Kcal/mol.Calculation also shows the existences of a minimum potential for the tautomer forms of the acid/7AI complex and the 7AI/7AI dimer in the ground state, and the tautomer complexes have stronger hydrogen bonding effect than their normal forms.
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Yu, Wei-Shan, and 游偉盛. "Excited-State Double Proton Transfer on 3-Substituted-7-Azaindole Analogues and Photoinduced Electron Transfer of New Type Donor-Bridge-Acceptor Molecules." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/84410813424643570922.
Full textAbstract:
博士國立中正大學
化學研究所
90
Abstract Unlike 7-azaindole consisting of the tetrameric configuration, 3-methyl-7-azaindole (3MAI) exists solely as intact double hydrogen-bonded dimeric forms in a single crystal. Both steady state and time-resolved measurements down to 8.0 K reveal remarkable deuterium isotope effects on the rate of excited-state double proton transfer (ESDPT) in the N(1)-deuterated 3MAI (3MAI-d) single crystal. The rates of ESDPT for the 3MAI-d dimer resolved at < 150 K are mainly governed by the proton tunneling mechanism. At < 12 K, the nearly temperature-independent ESDPT dynamics lead us to qualitatively deduce a barrier height of ~ 1.73 kcal/mol for the 3MAI-d dimer. The results provide an ideal model to investigate the intrinsic ESDPT dynamics for 7-azaindole analogues in which the structural information is well documented. The mechanism of excited-state double proton transfer (ESDPT) reaction of 7-azaindoles in pure water has been solved through design and syntheses of 3-Cyano-7-azaindole (3CAI) and its derivatives. Dual emission consisting of normal (lmax = 350 nm) and tautomer band (lmax = 475 nm) was resolved for 3CAI in pure water. Dynamical studies clearly revealed that the entire rise time of the tautomer emission of 850 ps is identical with the decay time (tf = 855 ps) of the normal emission. Remarkable deuterium isotope effect was observed in D2O where the rise time of 3.50 ns of the tautomer emission correlates well with the lifetime (3.45 ns) of the normal emission. The results lead us to conclude that dynamics of ESDPT with a rate of 850 ps-1 in water (or 3.50 ns-1 in D2O) originate from the entire ground-state solvated species, resolving a long-standing controversy regarding the mechanism of water catalyzed ESDPT in 7-azaindoles. We have demonstrated a new class of donor-{saturated hydrocarbon bridge}-acceptor (D-B-A) dyads based on a systematic approach to evaluate the corresponding photoinduced electron transfer process. Among these dyads heptacyclo[6.6.0.02,6.03,13.04,11.05,9.010,14]tetradecane (HCTD) was used as a unique spacer, which possesses a geometry of high symmetry (D2d), rigidity and linearity so that electron transfer processes can be examined between donor and acceptor substituents aligned along a straight line across the s-framework. In certain cases, via synthetic routes, the relative orientation of p-orbitals between donor and acceptor was adjusted to either a coplanar (0º) or perpendicular (90º) dihedral angle with respect to each other so that a comparative study could be made by tuning their relative electron coupling properties. The results in combination with theoretical approaches render valuable information on the spectroscopy and dynamics of excited-state electron transfer as functions of donor/acceptor electronic states, orientation as well as solvent properties.
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Martins, Maria Margarida Penhasco. "Investigation of the reactivity of aminopyridines on C-H activation reaction: a direct route to azaindoles." Master's thesis, 2019. http://hdl.handle.net/10362/87170.
Full textAbstract:
Azaindoles are relevant heterocyclic aromatic organic compounds that exhibit interesting biological activity. However, the azaindole core is challenging to achieved and most reported methods require the pre-functionalization of substrates. The C–H activation/functionalization reaction is an emergent topic, as organic scientists look at C–H bonds as reactive functional groups in metal-catalyzed reactions, avoiding the pre-functionalization of substrates and resulting in an approach that is less time and cost consuming plus environmentally friendly. C–H activation reactions are scarce regarding azaindole synthesis and, up to date, only two examples can be found in the literature which are restricted to the 7-azaindole isomer.
In this project, a methodology to attain the azaindole core through dual intramolecular C–H activation has been developed. For this purpose, very important synthetic intermediates – imines/enamines – have been prepared from C–N cross-coupling reaction of aminopyridines and α-bromostryrene. In an one-pot procedure, this unique C–N cross-coupling/C–H activation reaction allowed to obtain six azaindole structures (I.1–49%, I.2–9%, II.1–37%, III.1–64%, III.2–18%, IV.1–5%), with the first three reported for the first time.
Different catalytic systems for C–N cross-coupling and C–H activation reactions have been tested and manipulated in order to obtain the best conditions for each aminopyridine. A different reactivity was observed for each aminopyridine, depending on the presence of substituents and the substitution pattern in the pyridine ring.
For the C–N cross-coupling reaction, Pd2dba3/XPhos/t-BuONa (I.1/I.2, III.1/III.2 and IV.1) and Pd2dba3/XantPhos/t-BuONa (II.1) were applied and for the C–H activation reaction Pd(OAc)2/Cu(OAc)2/Cs2CO3 (I.1/I.2) and Pd(OAc)2/Ag2CO3/PivOH (II.1, III.1/III.2 and IV.1). The best yield obtained was for unsubstituted azaindole III.1/III.2, with a total conversion of 82%. Additionally, the addition of silver salts on the C–H activation reaction demonstrated to influence the regioselectivity. Ketone condensation with aminopyridines was tested as an alternative method to obtain the imine/enamine. It was concluded that the condensation reaction wasn’t efficient under the tested reaction conditions and better results might be obtained via a stepwise ketone condensation/C–H activation procedure.
Finally, a mechanistic proposal was undertaken based on NMR data, computational calculations and literature.
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Chen, Ting-Yu, and 陳庭郁. "Synthesis, Structures and the Photophysical Properties of Mono- and Dinuclear Platinum Complexes derived from C^C^C-Pincer Bis(carbene) Ligand with 1,8-naphthyridine and 7-azaindole coligands." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/49971686218366511864.
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Liu, Ying-Hsuan, and 劉穎瑄. "Part I: Synthesis and Study of Excited-State Intermolecular Proton Transfer in 7-Aminoquinoline and its DerivativesPart II: Synthesis and Study of Planarized Intramolecular Charge Transfer in 1-Amino-7-azaindole and its Derivatives." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/37v8w9.
Full textAbstract:
碩士國立臺灣大學
化學研究所
106
Part I 7-Aminoquinoline (7AQ) and its amino derivatives have been designed and synthesized to study their possible excited-state proton transfer (ESPT) reaction. Due to the far separation between the proton donor NR-H (D) and acceptor –N (A) sites, ESPT in 7AQ and analogues, if available, should proceed with solvent catalysis process. As a result, assisted by solvent molecules, TFA-7AQ, Ts-7AQ, Boc-7AQ and Ac-7AQ undergoes ESPT in alcohols such as methanol. Systematically probing ESPT spectroscopy and dynamics among all NR-H derivatives has been carried out in methanol. However, unlike the NR-H intramolecular system where the rate of excited-state intramolecular proton transfer (ESIPT) increases as increasing the NR-H acidity, the rate of solvent catalyzed ESPT was found to lack correlation with respect to the NR-H acidity among all NRH derivatives. The results are rationalized by the fact that increase of the NR-H acidity by the stronger electron withdrawing R group concurrently decreases the basicity of the quinolone nitrogen via resonance inductive effect. Part II In an aim to explore the mechanism of planarized intramolecular charge transfer (PLICT), we have synthesized 1-amino-7-azaindole (NH2-7AI) and N-amination derivatives, diMeN-7AI and AcNH-7AI. Because amino group is twisted in the ground states and becomes planarized in the excited states, this provides a powerful method to tune a very large Stokes shift and simultaneously emit high quantum yields in molecular spectroscopy. Measured in cyclohexane, apolar solvent, NH2-7AI and diMeN-7AI were investigated the large Stokes shifts amounting to about λ = 130 nm and 158 nm. This phenomenon can be rationally interpreted that in the excited states N-substituent molecules tend to delocalize electronic distribution via the lone pair electrons on nitrogen. Once the nitrogen lone pair electrons are coupled with aromatic π electrons through planarization, the molecules can potentially decrease excited-state energy. On the other hand, AcNH-7AI depicted a dual emission in cyclohexane at 323 nm and 380 nm, which could be implied as vertical state and planar state. In acetonitrile, polar solvent, AcNH-7AI was observed a large Stokes shift at 420 nm, progressing PLICT. Obviously, acetyl group is larger than dimethyl group, and the value of viscosity of cyclohexane is higher than that of acetonitrile, which results in the hinder of planarization. It is notable, consequently, that the size of substituent and viscosity of solvent are also the key elements of PLICT.
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Mortinho, Ana Cristina da Costa. "Novel synthetic routes towards azaindoles, Exploring one-pot metal-catalysed reactions." Master's thesis, 2018. http://hdl.handle.net/10362/53594.
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Azaindoles are heterocyclic compounds scarce in nature, although interesting scaffolds in medicinal chemistry so there is a need of developing sustainable synthetic methods to obtain these cores. To date several methods involving more than one metal-catalysed reaction, like C-N cross-coupling,Heck coupling or the Sonogashira have been developed towards azaindoles. However, these methods require the use of amino-halopyridines as starting materials, which are difficult to prepare.
This project aimed to surpass the need of functionalization of aminopyridines conceiving a fast and scalable one-pot methodology towards azaindole synthesis.
The first strategy envisaged a well-established reaction in our group, the C-N cross-coupling reaction, to prepare an imine/enamine in situ, followed by a C-H activation / oxidative cyclization reaction catalysed by a metal. The preliminary studies were made using 2,5-dimethylaniline and α-bromo styrene and other synthetized bromides. The indole compound II.2 was isolated in 50% yield, and under the same conditions different aminopyridines and bromides were tested using palladium catalysis in an unprecedented approach for azaindole synthesis. This strategy afforded only one regioisomer, a 4-azaindole (II.4) with a 70% yield and worked only with aminopyridines that possess electro-donating groups. However, this method proved to be limited to few substrates. Thus, an alternative approach was attempted in which the imines/enamines were formed in situ by condensation of an amine with a ketone, followed by C-H activation/oxidative cyclization catalysed by palladium. Preliminary studies were carried with 2,5-dimethylaniline and acetophenone and afforded the corresponding indole II.2 in 51% yield. Next, the same strategy was applied to aminopyridines. The reaction demonstrated to be effective when acetophenones were used. Thus, a variety of 4-azaindoles (14 examples, 13 synthesized in this thesis) were synthesized by this methodology with yields ranging from 24 % up to 96%, possessing electron-withdrawing and electron donating groups. The method developed consists on a simple protocol, a one-pot reaction, involving a C-H activation reaction scarcely explored in the synthesis of this class of compounds.
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Henning, Hendrik. "Novel synthetic methodology for the assembly of a-carbolines and 7-azaindoles." Thesis, 2018. https://hdl.handle.net/10539/25742.
Full textAbstract:
A thesis submitted to the
Faculty of Science,
University of the Witwatersrand,
Johannesburg,
in fulfilment of the requirements for the degree of
Doctor of Philosophy
Johannesburg, February 2018The a-carbolines and 7-azaindoles are part of a larger family of compounds derived from indoles and other heterocyclic compounds that are prevalent in nature often as biologically active compounds. The synthesis of a-carbolines and 7-azaindoles described in this thesis is built on several key reactions developed in our laboratories, namely the light mediated t-BuOK ring closure method used previously to form carbazoles, naphthalenes and anthracenes; as well as an acid mediated ring closure of acetylene containing 2- aminopyridines to form 7-azaindoles; and lastly catalytic palladium chemistry is used in some critical carbon carbon bond forming reactions, namely through the Sonogashira reaction. The bromine atoms on several 3-bromo-2-aminopyridine compounds is substituted with 1-ethynyl-2-methyl-benzene in a Sonogashira coupling reaction, followed by ring closure forming the respective 2-(2-methylphenyl)-1H -pyrrolo[2,3-b]pyridines (2-(o-tolyl)-1H -7- azaindoles). After formylation on the 3 position, forming 2-(2-methylphenyl)-1H -pyrrolo [2,3-b]pyridine-3-carbaldehydes (3-formyl-2-(o-tolyl)-1H -7-azaindoles), and N -benzylation on the 1 position, furnishing 1-benzyl-5-methyl-2-(2-methylphenyl)-pyrrolo[2,3-b]pyridine -3-carbaldehydes (3-formyl-2-(o-tolyl)-1-benzyl-7-azaindoles), the compounds were subjected to the light mediated ring closing methodology described, yielding 11-benzyl-benzo -a-carbolines (11-benzyl-11H -benzo[g]pyrido[2,3-b]indoles). The final debenzylation on 11-benzyl-benzo-a-carbolines (11-benzyl-11H -benzo[g]pyrido[2,3-b]indoles) synthesised furnished 11H -a-carbolines (11H -benzo[g]pyrido[2,3-b]indole). The novel synthesis of a-carbolines and 7-azaindoles through these methods proved successful, even though in low overall yields. The methodology was further extended to allow further substitution on a-carbolines. This was achieved by bromination on the initial 2-aminopyridine starting material in the 5 position, followed by iodination on the 3 position. The iodide of the 2-aminopyridine could then be selectively substituted using Sonogashira coupling as discussed, followed by Suzuki coupling on the bromide, in this case with 3,4- dimethoxy-phenyl boronic acid. The synthesis of 11H -3-(3,4-dimethoxyphenyl)-benzo-a- carboline was then completed using Suzuki coupling methodology to add the 3,4-dimethoxyphenyl functionality from (3,4-dimethoxyphenyl)boronic acid. The heterocycles synthesised in this thesis were tested against African sleeping sickness parasite Trypanosoma brucei. The compound 5-(3,4-dimethoxyphenyl)-2-(2-methylphenyl) -1H -pyrrolo[2,3-b]pyridine-3-carbaldehyde was found to have an IC50 value of 10 mM, with several others showing activity in the range of 12-27 mM. The antimalarial studies in contrast showed only one significant hit, 11-benzyl-3-(3,4dimethoxyphenyl)-benzo- a-carboline had an IC50 value of 26 mM. Overall, the study resulted in the successful synthesis of a-carbolines and 7-azaindoles, as well as the discovery of biologically active heterocycles effective against malaria and African sleeping sickness. These heterocycles could be used as lead compounds for further research.
MT 2018
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Cunha, José Carlos Ferreira da. "Expanding the toolbox of chemical tools to target malaria parasites with azaindoles." Master's thesis, 2022. http://hdl.handle.net/10362/133287.
Full textAbstract:
Malaria remains one of most lethal infectious diseases in the world. According to WHO, there were 228 million cases and 405,000 deaths in 2018 related to this mosquito-borne dis-ease caused by Plasmodium protozoan parasites. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Identifying new chemo-types with novel modes of action against different stages of the parasite lifecycle are now recognized as the defining traits of modern antimalarial drug discovery. Recently a set of indoles was found to present potent antimalarial activity and that represent a novel entry in the toolbox of chemical tools to target malaria parasites.
Azaindoles, which are bioisosteres of the indoles, and their derivatives, exhibit significant biological activities, and the use of this framework has contributed to the generation of new therapeutic agents.
This work describes the synthesis of nine novel azaindoles from available amino-ortho-halopyridines to expand the toolbox of modern antimalarial drugs. This procedure involved a palladium-catalyzed N-arylation followed by a Sonogashira reaction and sub-sequent cyclization in a one-pot manner.
The acquired azaindoles were tested for their bioactivity in an in vitro activity screening against Plasmodium falciparum and it was found that four out of nine azaindoles showed activity against the Plasmodium strain. To identify the binding mode and the favored binding proteins we applied machine learning algorithms to analyze the existing databases, which acknowledged the CGMP-dependent protein kinase as one of the most feasible targets. The subsequent docking studies on the promising protein are in agreement with the obtained bioactivity and indicate a high potential application of the new molecules as antimalarial agents.Malária é uma das doenças infeciosas letais que mais afeta a população mundial. De acordo com a organização mundial de saúde (OMS), existiram 228 milhões de casos e 405.000 mortes associadas a esta doença originária do mosquito e causada por parasitas protozoários Plasmodium. O desenvolvimento de novas terapias para combater o impacto da malaria tem sido particularmente desafiante, devido ao aparecimento de novas resistências generalizadas. O desenvolvimento de novos fármacos com atividade antimalárica, consiste agora na identificação de novos quimiotipos com diversos modos de ação inovadores para atuar nas diferentes fases da vida do parasita. Recentemente, um conjunto de composto contendo o núcleo de indole apresentaram potente atividade antimalárica e estes representam uma nova classe com interesse químico e biológico. Azaindoles, que são bioisoteres do indole, e os seus derivados apresentam uma atividade biológica significativa e o uso deste tipo de esqueleto-base tem contribuído para o aparecimento de novos agentes terapêuticos. Neste trabalho é descrita a síntese de nove azaindoles a partir de amino-orto-halopiridinas, de modo a explorar novos possíveis alvos terapêuticos com atividade antimalária. Este procedimento consistiu numa reação de etapa única envolvendo N-arilação catalisada por paládio, seguido de reação de Sonogashira e subsequente ciclização. A actividade biológica dos azaindoles sintetizados foi avaliada in vitro contra Plasmodium falciparum. Os resultados obtidos indicaram que quatro dos nove novos compostos apresentaram atividade contra a malária. Para identificar o binding mode e a proteína mais favorável foram usados algoritmos de machine learning para analisar as bases de dados, resultando na identificação da CGMP-dependent protein kinase como alvo promissor. Os estudos de docking estão concordantes com a bioatividade obtida, sugerindo um elevado potencial para as moléculas testadas como agentes antimaláricos.
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Su, Min-Jie, and 蘇民傑. "Synthesis and Structure-Activity Relationship of 1-Benzenesulfonyl-6-Azaindoles as Potent Anticancer Agents." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/88118937632470208405.
Full textAbstract:
碩士臺北醫學大學
藥學研究所
95
Two novel series of 7-anilino-6-azaindole-1-sulfonamides and 7-aryl-6- azaindole-1-sulfonamides based on N-[2-[(4-hydroxyphenyl)amino]-3- pyridinyl]-4-methoxybenzenesulfonamide (ABT-751) as a template were synthesized as potent antiproliferative agents. ABT-751 is an orally-active anticancer agent acting through the binding with the colchicine binding site on the tubulin. It is now undergoing human clinical trial. The synthesis of 7-anilino-6-azaindole-1-sulfonamide derivatives started from 2-bromo-3- nitropyridine, which was subjected to the vinyl magnesiumbromide to give 7-bromo-6-azaindole. The 7-bromo group was replaced with various aniline, and then treated with 4-methoxybenzenesulfonyl chloride to afford the 6-azaindole-1-sulfonamides.The synthesis of 7-aryl-6- azaindole-1- sulfonamide derivatives were prepared by a Suzuki reaction at 7-position, utilizing the 7-bromo-6-azaindole was treated with a variety of phenylboric acid to give the designed 7-aryl substituted 6-azaindoles. Compound 2, 3 , 4 , 5 , 9 , 10 , and 14 displayed moderate cytotoxicities with IC50 values of 278-886 nM. Compound 7 , 11 , and 13 showed a slight increase in activity with IC50 values of 150-200 nM as compared to ABT-751 (IC50 = 208 nM). The most potent compound 8 showed potent antiproliferative activity with IC50 values of 80 nM against human KB oral epidermoid carcinoma cell line. Structure- activity relationship information revealed that 7-aryl-6- azaindole-1- sulfonamide derivatives was more potent than 7-anilino-6-azaindole-1- sulfonamide derivatives. These findings have encouraged us to extensively explore the novel 6-azaindole-sulfonamides and further investigate their mode of action and mechanism.
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Ragie, Somayya. "The effect of novel compounds, imidazo [1,2-a] pyridines and azaindoles on colon cancer cell lines." Thesis, 2016. https://hdl.handle.net/10539/25793.
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Purificação, Sara Filipa Isidoro da. "Estudos sintéticos para preparação de compostos azaindólicos e indólicos." Master's thesis, 2016. http://hdl.handle.net/10362/21506.
Full textAbstract:
Os compostos orgânicos heterocíclicos constituem uma importante classe de compostos, fazendo parte integrante da estrutura de inúmeros fármacos disponíveis comercialmente. Este facto é um reflexo do papel central que o núcleo heterocíclico tem no desenho de fármacos, pois funciona como uma ferramenta para controlar e melhorar as propriedades farmacológicas, farmacocinéticas, toxicológicas e físico-químicas dos candidatos a fármacos e em última instância dos fármacos. Os azaindoles pertencem a esta classe, e são bioisosteres do núcleo de indole, uma estrutura privilegiada em química medicinal.
Os azaindoles possuem um anel de piridina e um anel de pirrole, fundidos por uma ligação C-C, constituindo núcleos promissores de novos fármacos. A nossa equipa tem vindo a explorar compostos heterocíclicos na procura de novos inibidores da COX-2, em particular compostos indólicos e mais recentemente os azaindoles. Devido à electrodeficiência do anel de piridina, os métodos clássicos de síntese de indoles são pouco eficientes ou não funcionam quando aplicados ao núcleo de azaindole. Por outro lado, os métodos sintéticos para preparação de azaindoles são escassos e os existentes apresentam inúmeras limitações.
Neste projecto foi estudada e desenvolvida uma nova e simples via para a síntese de azaindoles. Esta nova abordagem consistiu numa reacção em cascata envolvendo um acoplamento cruzado C-N e uma reacção de Heck de aminopiridinas halogenadas e brometos de vinilo comerciais, catalisada por paládio. O estudo envolveu a pesquisa das condições reaccionais, tendo-se preparado os quatro isómeros de azaindole, 4-, 5-, 6- e 7-azaindole com rendimentos bons a elevados (máximo 86%). A reactividade de diversas aminopiridinas halogenadas bem como a influência de substituintes no brometo foram analisadas.
Foram ainda preparadas N-fenil halo-aminopiridinas com rendimentos bons a excelentes (79 – 99 %) através de reacções de acoplamento cruzado C-N catalisado por paládio e foram investigados diversas abordagens para preparação das N-benzil halo-aminopiridinas. O melhor método revelou ser o que envolveu uma aminação redutiva na ausência de ácido acético, tendo-se isolado as aminopiridinas N-benziladas com rendimentos moderados a bons (36 - 77%). No entanto, a reacção em cascata, nas condições usadas, funcionou apenas para as aminopiridinas simples.
Estudos preliminares de docking conduziram a uma proposta de compostos de azaindole com um determinado padrão de substituição. Uma vez que o azaindole e o indole são dois núcleos muito semelhantes, na segunda parte deste trabalho explorou-se um método de indolização recentemente reportado, para preparação de compostos indólicos com um padrão de substituição análogo ao proposto pelo docking para os azaindoles. Desta forma irá realizar-se um estudo da relação estrutura-actividade. Este método envolveu a formação de imina e posterior ciclização oxidativa catalisada por paládio. Foram preparados os indoles 10d e 10c com um rendimento de 1% (produto puro) e 62%, respectivamente.