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dc.contributor.authorFerreira, Larissa de Almeida Peixoto
dc.date.accessioned2023-12-22T03:03:52Z-
dc.date.available2023-12-22T03:03:52Z-
dc.date.issued2021-04-16
dc.identifier.citationFERREIRA, Larissa de Almeida Peixoto. Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer. 2021. 181 f. Dissertação (Mestrado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, 2021.por
dc.identifier.urihttps://rima.ufrrj.br/jspui/handle/20.500.14407/14639-
dc.description.abstractA doença de Alzheimer (DA) é uma doença neurodegenerativa progressiva que possui uma patogênese complexa, induzindo a perda de memória e distúrbios cognitivos, que geralmente se apresenta na terceira idade. As cumarinas e imidazopiridinas (IM) são classes de compostos com ampla atuação farmacológica e existem diversos estudos promissores relacionados ao tratamento da DA, atuando em vários alvos como acetilcolinesterase (AChE), butirilcolinesterase (BuChE), agregação de placas β-amilóides (Aβ) e entre outros. Assim, o objetivo geral deste trabalho é a síntese de novas 3-(imidazo[1,2-α]piridin-2-il)-cumarinas, com base em trocas clássicas de bioisosterismo de grupos 4-(dimetilamino)fenila por imidazopiridinas (IM) como possíveis inibidores de colinesterases para o tratamento da DA. A primeira série originou-se pela síntese das 3-(imidazo[1,2-a]piridinas)-cumarinas (66a-d) envolvendo 5 etapas reacionais: síntese das 3-acetil-cumarinas (67a-c) (rendimento de 70% a 90%) (etapa 1), α-bromação das 3-acetil-cumarinas (rendimento de 51 a 73%) (etapa 2), formação do núcleo da IM (etapa 3) (rendimento de 64 a 69%), alquilação das IMs com conversões de 74% a 88% (etapa 4) e, por fim, a etapa de aminação com a formação dos compostos finais (66a-d). A segunda série veio da síntese de 3-(imidazo[1,2-α]piridinas-9'-etilcarboxilato)-cumarinas, envolvendo etapas de condensação Knoevenagel para formação de compostos com núcleo cumarínico (89) (rendimento de 86%), O-alquilação (93a-d) (rendimentos de 30 a 74%), formação do núcleo das IMs (102a-d) (rendimentos de 42 a 74%) e aminação (103a-d) (rendimentos de 31% a 79%). Screening inicial a uma concentração fixa de 30 μM, para dois compostos finais 66b e 103b, demonstrou uma inibição enzimática de aproximadamente 91,7% (AChE) / 92,4% (BuChE) e 98,1% (AChE) / 88,6%(BuChE), respectivamente. Além da atividade foram realizados estudos in sílico de modelagem molecular e parâmetros ADME. Com base nesses resultados preliminares, novos compostos estão sendo sintetizados, e o CI50 e a cinética enzimática frente as colinesterases serão determinadas.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.subjectDoença de Alzheimerpor
dc.subjectCumarinaspor
dc.subjectImidazo-piridinaspor
dc.subjectInibidores de AChE e BuChEpor
dc.subjectAlzheimer's diseaseeng
dc.subjectCoumarinseng
dc.subjectImidazo-pyridineseng
dc.subjectAChE and BuChE inhibitorseng
dc.titleSíntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimerpor
dc.typeDissertaçãopor
dc.description.abstractOtherAlzheimer's disease (AD) is a progressive neurodegenerative disease that has complex pathogenesis, inducing memory loss and cognitive disorders, which usually present in old age. The coumarins and imidazopyridines (IM) are classes of compounds with wide pharmacological activity and several promising studies related to the treatment of AD acting on several targets such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), aggregation of β-amyloid plaques (Aβ), and among others. Thus, the general objective of this work is the synthesis of new 3- (imidazo [1,2-α] pyridin-2-yl) -coumarins, based on classic bioisosterism of 4-(dimethylamino) phenyl groups by imidazopyridines (IM) as possible cholinesterase inhibitors for the treatment of AD. The first series is originated from the synthesis of 3-(imidazo [1,2-α] pyridines)-coumarins (66a-d) involving 5 reaction steps: synthesis of 3-acetyl-coumarins (67a-c) (yields 70 % to 90%) (step 1), α-bromination of 3-acetyl-coumarins (yields 51 to 73%) (step 2), formation of the IM nucleus (step 3) (64 to 69% yield), alkylation of the IMs with conversions of 74% to 88% (step 4) and, finally, the amination step with the formation of the final compounds (66a-b). The second series came from the synthesis of 3-(imidazo [1,2-α] pyridines-9'-ethylcarboxylate)-coumarins, involving Knoevenagel condensation steps to form compounds with coumarin nucleus (89) (86% yield), O-alkylation (93a-d) (yields from 30 to 74%), core formation of MIs (102a-d) (yields from 42 to 74%) and amination (103a-d) (yields from 31% to 79%). Initial screening at a fixed concentration of 30 μM, for two final compounds 66b and 103b, showed an enzymatic inhibition of approximately 91.7% (AChE) / 92.4% (BuChE) and 98.1% (AChE) / 88, 6% (BuChE), respectively. In addition to the activity, in sílico studies of molecular modeling and ADME parameters were carried out. Based on these preliminary results, new compounds are being synthesized, the IC50 and the enzymatic kinetics against cholinesterases will be determined.eng
dc.contributor.advisor1Kümmerle, Arthur Eugen
dc.contributor.advisor1ID053.978.487-78por
dc.contributor.advisor1Latteshttp://lattes.cnpq.br/5598000938584486por
dc.contributor.referee1Kummerle, Arthur Eugen
dc.contributor.referee2Lacerda, Renata Barbosa
dc.contributor.referee3Barbosa, Maria Leticia de Castro
dc.contributor.referee4Graebin, Cedric Stephan
dc.contributor.referee5Alves, Mariana Amaral
dc.creator.ID155.369.077-00por
dc.creator.Latteshttp://lattes.cnpq.br/6900569101255090por
dc.publisher.countryBrasilpor
dc.publisher.departmentInstituto de Químicapor
dc.publisher.initialsUFRRJpor
dc.publisher.programPrograma de Pós-Graduação em Químicapor
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dc.subject.cnpqQuímicapor
dc.thumbnail.urlhttps://tede.ufrrj.br/retrieve/73072/2021%20-%20Larissa%20de%20Almeida%20Peixoto%20Ferreira.pdf.jpg*
dc.originais.urihttps://tede.ufrrj.br/jspui/handle/jspui/6552
dc.originais.provenanceSubmitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2023-05-02T20:28:22Z No. of bitstreams: 1 2021 - Larissa de Almeida Peixoto Ferreira.pdf: 4843012 bytes, checksum: 6fb92c6e4ea6804eccad02e5c99fde21 (MD5)eng
dc.originais.provenanceMade available in DSpace on 2023-05-02T20:28:22Z (GMT). No. of bitstreams: 1 2021 - Larissa de Almeida Peixoto Ferreira.pdf: 4843012 bytes, checksum: 6fb92c6e4ea6804eccad02e5c99fde21 (MD5) Previous issue date: 2021-04-16eng
Appears in Collections:Mestrado em Química

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