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dc.contributor.authorNadur, Nathalia Fonseca
dc.date.accessioned2023-12-22T03:05:07Z-
dc.date.available2023-12-22T03:05:07Z-
dc.date.issued2020-02-05
dc.identifier.citationNADUR, Nathalia Fonseca. Síntese e avaliação farmacológica de novas 3-(1,2,3-triazol)-cumarinas planejadas para o tratamento da Doença de Alzheimer. 2020. 165 f. Dissertação (Mestrado em Química) - Universidade Federal Rural do Rio de Janeiro, Seropédca, 2020.por
dc.identifier.urihttps://rima.ufrrj.br/jspui/handle/20.500.14407/14729-
dc.description.abstractA Doença de Alzheimer (DA) caracteriza-se por ser um distúrbio neurodegenerativo progressivo e irreversível de memória e outras funções cognitivas, afetando o funcionamento ocupacional e social. O uso de compostos híbridos com potencial inibidor para mais de um alvo, como a enzima acetilcolinesterase (AChE) e a agregação de placas β-Amiloides (Aβ), vem sendo apontado como de grande valia para o tratamento da DA devido à possiblidade de inibir simultaneamente alvos que contribuem para a instalação e manutenção da doença. A AChE atua no controle dos níveis do neurotransmissor acetilcolina (ACh) na fenda sináptica, o qual está envolvido nos processos de aprendizagem e memória. A agregação de placas Aβ é uma das principais responsáveis pela morte neuronal. Estudos recentes publicados pelo nosso grupo de pesquisa (LaDMol-QM) demostraram o núcleo alquilamino-cumarina como um potencial inibidor da enzima AChE e agregação de placas Aβ. Esses resultados inspiraram a série planejada dos novos derivados 3-(1,2,3-triazol)-cumarínicos propostos nesse trabalho, baseando-se em requisitos estruturais presentes nestes inibidores alquilamino-cumarínicos, onde se propôs a avaliação de diferentes grupamentos alquilamino cíclico, a avaliação de diferentes tamanhos de cadeia alquílica entre o grupamento alquilamino e o núcleo cumarínico, a adição do grupamento 1,2,3-triazol com diferentes substituintes. Os compostos foram sintetizados em rendimentos de razoáveis a bons a partir das reações de: síntese da 7-hidroxicumarina, O-alquilação da 7-hidroxicumarina com uma série de dibrometos com diferentes tamanhos de cadeia, a bromação da posição 3 do núcleo cumarínico das 7-bromoalcoxi-cumarina, reação de acoplamento cruzado de Sonogashira a partir das 3-bromo-7-bromoalcoxi-cumarina, desproteção do grupamento trimetilsilila da 7-bromoalcoxi-3-((trimetilsilil)etenil)-cumarina, reação de cicloadição 1,3-dipolar catalisada por cobre (CuAAc), utilizando 3-etenil-7-bromoalcoxi-cumarina e azidas aromáticas, aminação da cadeia alquílica das 3-(1H-1,2,3-triazol-4-R1)-7-(aminoalcoxi)-cumarina. Os compostos obtidos foram purificados e, então, caracterizados por técnicas espectroscópicas (RMN 1H e 13C). Todos os compostos sintetizados foram capazes de inibir a AChE, ensaiados e apresentaram valores de CI50 variando de 0,006 a 4,79 μM.por
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorpor
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológicopor
dc.description.sponsorshipFAPERJ - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiropor
dc.formatapplication/pdf*
dc.languageporpor
dc.publisherUniversidade Federal Rural do Rio de Janeiropor
dc.rightsAcesso Abertopor
dc.subjectAlzheimerpor
dc.subjectCumarinaspor
dc.subjectInibidores de colinesterásicospor
dc.subjectInibidores de agregação de placas β-amilóidepor
dc.subjectCoumarinseng
dc.subjectCholinesterase inhibitorseng
dc.subjectβ-Amyloid plaques aggregation inhibitorseng
dc.titleSíntese e avaliação farmacológica de novas 3-(1,2,3-triazol)-cumarinas planejadas para o tratamento da Doença de Alzheimerpor
dc.typeDissertaçãopor
dc.description.abstractOtherAlzheimer’s Disease (AD) is a progressive and irreversible neurodegenerative disorder, which affects memory and other cognitive functions, also affecting ocupational and social aspects. Using hybrid compounds with inhibition potential to multiple targets, like acetylcholinesterase enzyme (AChE) and β-amyloid peptides plaques aggregation (Aβ), has been observed as a high value objective for AD treatment due to possibilty to inhibit simultaneously different targets that contribute to instalation and maintenance of the disease. AChE acts controlling levels of the neurotransmitter acetylcholine (ACh) in synaptic cleft, that plays a role in the processes of learning and memory developing. The aggregation of Aβ plaques is one of the main responsible for neuronal death. Recent published studies by our research group (LaDMol-QM) revealed the alkylamino-coumarin nucleus as a potential inhibitor of AChE and Aβ plaques aggregation. These results inspired a planned developing serie of new 3-(1,2,3-triazole)-coumarin derivatives purposed in this paper, based in structural aspects existent in those alkylamino-coumarin inhibitors, where it was purposed an evaluation of different cyclic alkylamino groups, also the evaluation of different sizes of alkyl chain between the alkylamino group and coumarin group, the addition of 1,2,3-triazole group with different substituents. The compounds were synthesized in yields reasonable to good from reactions of: synthesis of 7-hydroxycoumarin, O-alkylation of 7-hydroxycoumarin with a dibromides serie with different chain sizes, bromation of position 3 of coumarin nucleus of the 7-bromoalkoxy-coumarin, reaction of Sonogashira’s cross-coupling from 3-bromo-7-bromoalkoxy-coumarin, deprotection of trimethylsilyl group of 7-bromoalkoxy-3-((trimethylsilyl)ethenyl)-coumarin, reaction of 1,3-dipolar cycloaddition copper catalyzed (CuAAC), using 3-ethenyl-7-bromo-alkoxy-coumarin and aromatic azides, amination of alkyl chain of 3-(1H-1,2,3-triazol-4,R1)-7-(aminoalkoxy)-coumarin. The compounds were purified and then characterized by spectroscopic techniques (NMR 1H e 13C). As a result, all synthesized compounds were able to inhibit AChE, based on assays and presented IC50 values from 0,006 to 4,79 μM.eng
dc.contributor.advisor1Kümmerle, Arthur Eugen
dc.contributor.advisor1ID053.978.487-78por
dc.contributor.advisor1Latteshttp://lattes.cnpq.br/5598000938584486por
dc.contributor.referee1Kümmerle, Arthur Eugen
dc.contributor.referee2Rocha, David Rodrigues da
dc.contributor.referee3Graebin, Cedric Stephan
dc.creator.ID426.092.868-64por
dc.creator.Latteshttp://lattes.cnpq.br/4851384421417833por
dc.publisher.countryBrasilpor
dc.publisher.departmentInstituto de Químicapor
dc.publisher.initialsUFRRJpor
dc.publisher.programPrograma de Pós-Graduação em Químicapor
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