Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer
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| Data de Publicação: | 2021 |
| Tipo de documento: | Dissertação |
| Idioma: | por |
| Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFRRJ |
| Texto Completo: | https://rima.ufrrj.br/jspui/handle/20.500.14407/14639 |
Resumo: | A 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. |
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Ferreira, Larissa de Almeida PeixotoKümmerle, Arthur Eugen053.978.487-78http://lattes.cnpq.br/5598000938584486Kummerle, Arthur EugenLacerda, Renata BarbosaBarbosa, Maria Leticia de CastroGraebin, Cedric StephanAlves, Mariana Amaral155.369.077-00http://lattes.cnpq.br/69005691012550902023-12-22T03:03:52Z2023-12-22T03:03:52Z2021-04-16FERREIRA, 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.https://rima.ufrrj.br/jspui/handle/20.500.14407/14639A 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.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPERJ - Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de JaneiroAlzheimer'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.application/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de QuímicaDoença de AlzheimerCumarinasImidazo-piridinasInibidores de AChE e BuChEAlzheimer's diseaseCoumarinsImidazo-pyridinesAChE and BuChE inhibitorsQuímicaSíntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimerinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisADI. ALZHEIMER’S DISEASE INTERNATIONAL. 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Imidazopyridine-based selective and multifunctional ligands of biological targets associated with psychiatric and neurodegenerative diseases. European Journal of Medicinal Chemistry, v. 181, p. 111569, 2019.. VATANABE, I. P.; MANZINE, P. R.; COMINETTI, M. R. Historic concepts of dementia and Alzheimer's disease: From ancient times to the present. Revue neurologique, v. 176, n. 3, p. 140-147, 2020. VENTURA, Ana LM et al. Sistema colinérgico: revisitando receptores, regulação e a relação com a doença de Alzheimer, esquizofrenia, epilepsia e tabagismo. Archives of Clinical Psychiatry (São Paulo), v. 37, n. 2, p. 66-72, 2010. VERNUGOPALA, K. N.; RASHMI, V.; ODHAV, B. Review on natural coumarin lead compounds for their pharmacological activity. Hindawi Publishing Corporation, p.14, 2013. VOLOBOUEVA, Ludmila A.; GIFFARD, Rona G. Inflammation, mitochondria, and the inhibition of adult neurogenesis. Journal of neuroscience research, v. 89, n. 12, p. 1989-1996, 2011. WANG, Yali et al. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer’s disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. Journal of enzyme inhibition and medicinal chemistry, v. 31, n. 3, p. 389-397, 2016. YAKOUB, Kirsten et al. Structure–Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors. Journal of medicinal chemistry, v. 61, n. 5, p. 1951-1968, 2018. YIANNOPOULOU, Konstantina G.; PAPAGEORGIOU, Sokratis G. Current and future treatments for Alzheimer’s disease. Therapeutic advances in neurological disorders, v. 6, n. 1, p. 19-33, 2013. ZHAO, Jie; O'CONNOR, Tracy; VASSAR, Robert. The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis. 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| dc.title.por.fl_str_mv |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| title |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| spellingShingle |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer Ferreira, Larissa de Almeida Peixoto Doença de Alzheimer Cumarinas Imidazo-piridinas Inibidores de AChE e BuChE Alzheimer's disease Coumarins Imidazo-pyridines AChE and BuChE inhibitors Química |
| title_short |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| title_full |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| title_fullStr |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| title_full_unstemmed |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| title_sort |
Síntese e avaliação farmacológica de novas 3-(imidazo[1,2-α]piridinas)-cumarinas planejadas para o tratamento da Doença de Alzheimer |
| author |
Ferreira, Larissa de Almeida Peixoto |
| author_facet |
Ferreira, Larissa de Almeida Peixoto |
| author_role |
author |
| dc.contributor.author.fl_str_mv |
Ferreira, Larissa de Almeida Peixoto |
| dc.contributor.advisor1.fl_str_mv |
Kümmerle, Arthur Eugen |
| dc.contributor.advisor1ID.fl_str_mv |
053.978.487-78 |
| dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5598000938584486 |
| dc.contributor.referee1.fl_str_mv |
Kummerle, Arthur Eugen |
| dc.contributor.referee2.fl_str_mv |
Lacerda, Renata Barbosa |
| dc.contributor.referee3.fl_str_mv |
Barbosa, Maria Leticia de Castro |
| dc.contributor.referee4.fl_str_mv |
Graebin, Cedric Stephan |
| dc.contributor.referee5.fl_str_mv |
Alves, Mariana Amaral |
| dc.contributor.authorID.fl_str_mv |
155.369.077-00 |
| dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/6900569101255090 |
| contributor_str_mv |
Kümmerle, Arthur Eugen Kummerle, Arthur Eugen Lacerda, Renata Barbosa Barbosa, Maria Leticia de Castro Graebin, Cedric Stephan Alves, Mariana Amaral |
| dc.subject.por.fl_str_mv |
Doença de Alzheimer Cumarinas Imidazo-piridinas Inibidores de AChE e BuChE |
| topic |
Doença de Alzheimer Cumarinas Imidazo-piridinas Inibidores de AChE e BuChE Alzheimer's disease Coumarins Imidazo-pyridines AChE and BuChE inhibitors Química |
| dc.subject.eng.fl_str_mv |
Alzheimer's disease Coumarins Imidazo-pyridines AChE and BuChE inhibitors |
| dc.subject.cnpq.fl_str_mv |
Química |
| description |
A 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. |
| publishDate |
2021 |
| dc.date.issued.fl_str_mv |
2021-04-16 |
| dc.date.accessioned.fl_str_mv |
2023-12-22T03:03:52Z |
| dc.date.available.fl_str_mv |
2023-12-22T03:03:52Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| format |
masterThesis |
| status_str |
publishedVersion |
| dc.identifier.citation.fl_str_mv |
FERREIRA, 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. |
| dc.identifier.uri.fl_str_mv |
https://rima.ufrrj.br/jspui/handle/20.500.14407/14639 |
| identifier_str_mv |
FERREIRA, 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. |
| url |
https://rima.ufrrj.br/jspui/handle/20.500.14407/14639 |
| dc.language.iso.fl_str_mv |
por |
| language |
por |
| dc.relation.references.por.fl_str_mv |
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