Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer
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| Data de Publicação: | 2018 |
| 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/20.500.14407/14615 |
Resumo: | A Doença de Alzheimer (DA) caracteriza-se por um distúrbio neurodegenerativo que provoca uma deterioração global, progressiva e irreversível de diversas funções cognitivas (memória, atenção, concentração, linguagem, pensamento, entre outras), dificultando a realização das atividades de vida diária. No que se diz respeito ao tratamento da DA, vem sendo apontado como de grande valia 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), devido à possibilidade de inibir simultaneamente dois ou mais fatores que contribuem para a instalação e evolução 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. Desta forma, o objetivo deste trabalho foi sintetizar compostos cumarínicos análogos a protótipos alquilamino-indanonas, descritos como inibidores da enzima AChE e da agregação de placas Aβ. O planejamento das séries foi baseado: 1- na manutenção do grupamento alquilamino cíclico; 2- na troca do núcleo indanona pelo cumarínico, através do isosterismo não-clássico de expansão de anéis. Os compostos foram sintetizados em rendimentos de razoáveis a bons a partir das reações de: O-alquilação da 7-hidroxi-cumarina; bromação da posição 3 das 7-bromoalcoxi-cumarinas; aminação da cadeia alquílica das 3- bromo-7-bromoalcoxi-cumarinas; reação de acoplamento de Suzuki a partir das 3-bromo-7- aminoalcoxi-cumarinas; reação de acoplamento de Buchwald a partir da 3-bromo-7- aminoetoxi-cumarina. Os compostos obtidos foram purificados e, então, caracterizados por técnicas espectroscópicas (RMN 1H e 13C) e espectrometria de massas de alta resolução. Todos os compostos sintetizados foram capazes de inibir a AChE seletivamente frente à BChE, em que o composto mais ativo apresentou CI50 = 0,02 µM e seletividade de 337 (BChE CI50/AChE CI50), perfil muito semelhante ao fármaco referência donepezila (AChE CI50 = 0,007 µM e seletividade de 341). Adicionalmente, os compostos mostraram perfil de inibição mista para ambas as colinesterases, o que foi corroborado por análises de docking molecular que demonstraram a interação dos compostos com os sítios catalítico (CAS) e periférico (PAS). |
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Souza, Gabriela Alves deKümmerle, Arthur Eugen053.978.487-78http://lattes.cnpq.br/5598000938584486Kümmerle, Arthur Eugen053.978.487-78http://lattes.cnpq.br/5598000938584486Alves, Marina Amaralhttps://orcid.org/0000-0002-8188-5554http://lattes.cnpq.br/0945374845574106Sant'Anna, Carlos Mauricio Rabello dehttps://orcid.org/0000-0003-1989-5038http://lattes.cnpq.br/2087099684752643127.252.887-11http://lattes.cnpq.br/09135446571188172023-12-22T03:03:31Z2023-12-22T03:03:31Z2018-11-21SOUZA, Gabriela Alves de. Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer. 2018. 150 f. Dissertação (Mestrado em Quìmica) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2018.https://rima.ufrrj.br/jspui/handle/20.500.14407/14615A Doença de Alzheimer (DA) caracteriza-se por um distúrbio neurodegenerativo que provoca uma deterioração global, progressiva e irreversível de diversas funções cognitivas (memória, atenção, concentração, linguagem, pensamento, entre outras), dificultando a realização das atividades de vida diária. No que se diz respeito ao tratamento da DA, vem sendo apontado como de grande valia 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), devido à possibilidade de inibir simultaneamente dois ou mais fatores que contribuem para a instalação e evolução 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. Desta forma, o objetivo deste trabalho foi sintetizar compostos cumarínicos análogos a protótipos alquilamino-indanonas, descritos como inibidores da enzima AChE e da agregação de placas Aβ. O planejamento das séries foi baseado: 1- na manutenção do grupamento alquilamino cíclico; 2- na troca do núcleo indanona pelo cumarínico, através do isosterismo não-clássico de expansão de anéis. Os compostos foram sintetizados em rendimentos de razoáveis a bons a partir das reações de: O-alquilação da 7-hidroxi-cumarina; bromação da posição 3 das 7-bromoalcoxi-cumarinas; aminação da cadeia alquílica das 3- bromo-7-bromoalcoxi-cumarinas; reação de acoplamento de Suzuki a partir das 3-bromo-7- aminoalcoxi-cumarinas; reação de acoplamento de Buchwald a partir da 3-bromo-7- aminoetoxi-cumarina. Os compostos obtidos foram purificados e, então, caracterizados por técnicas espectroscópicas (RMN 1H e 13C) e espectrometria de massas de alta resolução. Todos os compostos sintetizados foram capazes de inibir a AChE seletivamente frente à BChE, em que o composto mais ativo apresentou CI50 = 0,02 µM e seletividade de 337 (BChE CI50/AChE CI50), perfil muito semelhante ao fármaco referência donepezila (AChE CI50 = 0,007 µM e seletividade de 341). Adicionalmente, os compostos mostraram perfil de inibição mista para ambas as colinesterases, o que foi corroborado por análises de docking molecular que demonstraram a interação dos compostos com os sítios catalítico (CAS) e periférico (PAS).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 neurodegenerative disorder that causes a general, progressive and irreversible deterioration of several cognitive functions (memory, attention, concentration, language, thought, among others), making it difficult to perform daily activities . , The use of hybrid compounds for the treatment of AD with inhibitory potential for more than one target, such as the acetylcholinesterase enzyme (AChE) and the aggregation of β-amyloid plaques (Aβ), is very promising, due to the possibility of inhibiting simultaneously two or more factors that contribute to the establishment and evolution of the disease. AChE modules the levels of the neurotransmitter acetylcholine (ACh) in the synaptic cleft, factor that is involved in the learning and memory processes. The aggregation of Aβ plaques is one of the main causes for neuronal death. Thus, this work aims on the synthesis of coumarin compounds analogous to alkylamino-indanone prototypes, described as inhibitors for both AChE enzyme and Aβ plaques aggregation. The design of the series was based on: 1- the maintenance of the cyclic alkylamino group; 2- in the exchange of the indanone nucleus by the coumarin, through nonclassical isosterism of ring expansion. The synthesis of compounds involved: O-alkylation of 7-hydroxycoumarin; bromination at the 3-position of the 7-bromoalkoxycoumarins; amination of the alkyl chain of 3-bromo-7-bromoalkoxycoumarins; Suzuki coupling reaction of the 3- bromo-7-aminoalkoxycoumarins; Buchwald coupling reaction of the 3-bromo-7-aminoethoxycoumarins; all reactions presented regular to good yields. After purification, the characterization of compounds by spectroscopic techniques (1H and 13C NMR) and high resolution mass spectrometry confirmed the products. All synthesized compounds were able to inhibit AChE selectively against BChE, in which the most active compound presented IC50 = 0,02 µM and selectivity of 337 (BChE IC50 / AChE IC50), acting very similarly to reference drug donepezil (AChE IC50 = 0,007 µM and selectivity of 341). Additionally, the compounds showed mixed inhibition profile for both cholinesterases, which was corroborated by molecular docking analyzes that demonstrated the interaction of the compounds with the catalytic (CAS) and peripheral (PAS) sites.application/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de QuímicaCumarinaDoença de AlzheimerInibidores de AChEInibidores de agregação de placas AβCoumarinAlzheimer's DiseaseAChE InhibitorsAβ Plate Aggregation InhibitorsQuímicaSíntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de AlzheimerSynthesis of alkylaminocoumarin compounds designed as inhibitors of acetylcholinesterase and β-amyloid plaque aggregation for the treatment of Alzheimer's diseaseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisALZHEIMER’S ASSOCIATION. 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Journal of Pharmacology and Experimental Therapeutics, 306(3), p. 821-827, 2003. 89 TIWARI, P.; DWIVEDI, S.; SINGH, M. P.; MISHRA, R.; CHANDY, A. Basic and modern concepts on cholinergic receptor: A review. Asian Pacific journal of tropical disease, 3(5), p. 413-420, 2013. TRKOVNIK, M.; IVEZIC, Z. J. Syntheses of some new coumarin‐quinolone carboxylic acids. Journal of Heterocyclic Chemistry, 37(1), p. 137-141, 2000. WANG, X., TIAN, J., YONG, K. T., ZHU, X., LIN, M. C. M., JIANG, W., LI, J., HUANG, Q. LIN, G. Immunotoxicity assessment of CdSe/ZnS quantum dots in macrophages, lymphocytes and BALB/c mice. Journal of nanobiotechnology, 14(1), p. 10, 2016. XICOTA, L.; RODRÍGUEZ-MORATÓ, J.; DIERSSEN, M.; DE LA TORRE, R. Potential role of (-)-epigallocatechin-3-gallate (EGCG) in the secondary prevention of Alzheimer disease. Current drug targets, 18(2), p.174-195, 2017. YAMADA, M.; CHIBA, T.; SASABE, J., NAWA, M., TAJIMA, H., NIIKURA, T.; NISHIMOTO, I. 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| dc.title.por.fl_str_mv |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| dc.title.alternative.eng.fl_str_mv |
Synthesis of alkylaminocoumarin compounds designed as inhibitors of acetylcholinesterase and β-amyloid plaque aggregation for the treatment of Alzheimer's disease |
| title |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| spellingShingle |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer Souza, Gabriela Alves de Cumarina Doença de Alzheimer Inibidores de AChE Inibidores de agregação de placas Aβ Coumarin Alzheimer's Disease AChE Inhibitors Aβ Plate Aggregation Inhibitors Química |
| title_short |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| title_full |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| title_fullStr |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| title_full_unstemmed |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| title_sort |
Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer |
| author |
Souza, Gabriela Alves de |
| author_facet |
Souza, Gabriela Alves de |
| author_role |
author |
| dc.contributor.author.fl_str_mv |
Souza, Gabriela Alves de |
| 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 |
Kümmerle, Arthur Eugen |
| dc.contributor.referee1ID.fl_str_mv |
053.978.487-78 |
| dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/5598000938584486 |
| dc.contributor.referee2.fl_str_mv |
Alves, Marina Amaral |
| dc.contributor.referee2ID.fl_str_mv |
https://orcid.org/0000-0002-8188-5554 |
| dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/0945374845574106 |
| dc.contributor.referee3.fl_str_mv |
Sant'Anna, Carlos Mauricio Rabello de |
| dc.contributor.referee3ID.fl_str_mv |
https://orcid.org/0000-0003-1989-5038 |
| dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/2087099684752643 |
| dc.contributor.authorID.fl_str_mv |
127.252.887-11 |
| dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/0913544657118817 |
| contributor_str_mv |
Kümmerle, Arthur Eugen Kümmerle, Arthur Eugen Alves, Marina Amaral Sant'Anna, Carlos Mauricio Rabello de |
| dc.subject.por.fl_str_mv |
Cumarina Doença de Alzheimer Inibidores de AChE Inibidores de agregação de placas Aβ |
| topic |
Cumarina Doença de Alzheimer Inibidores de AChE Inibidores de agregação de placas Aβ Coumarin Alzheimer's Disease AChE Inhibitors Aβ Plate Aggregation Inhibitors Química |
| dc.subject.eng.fl_str_mv |
Coumarin Alzheimer's Disease AChE Inhibitors Aβ Plate Aggregation Inhibitors |
| dc.subject.cnpq.fl_str_mv |
Química |
| description |
A Doença de Alzheimer (DA) caracteriza-se por um distúrbio neurodegenerativo que provoca uma deterioração global, progressiva e irreversível de diversas funções cognitivas (memória, atenção, concentração, linguagem, pensamento, entre outras), dificultando a realização das atividades de vida diária. No que se diz respeito ao tratamento da DA, vem sendo apontado como de grande valia 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), devido à possibilidade de inibir simultaneamente dois ou mais fatores que contribuem para a instalação e evolução 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. Desta forma, o objetivo deste trabalho foi sintetizar compostos cumarínicos análogos a protótipos alquilamino-indanonas, descritos como inibidores da enzima AChE e da agregação de placas Aβ. O planejamento das séries foi baseado: 1- na manutenção do grupamento alquilamino cíclico; 2- na troca do núcleo indanona pelo cumarínico, através do isosterismo não-clássico de expansão de anéis. Os compostos foram sintetizados em rendimentos de razoáveis a bons a partir das reações de: O-alquilação da 7-hidroxi-cumarina; bromação da posição 3 das 7-bromoalcoxi-cumarinas; aminação da cadeia alquílica das 3- bromo-7-bromoalcoxi-cumarinas; reação de acoplamento de Suzuki a partir das 3-bromo-7- aminoalcoxi-cumarinas; reação de acoplamento de Buchwald a partir da 3-bromo-7- aminoetoxi-cumarina. Os compostos obtidos foram purificados e, então, caracterizados por técnicas espectroscópicas (RMN 1H e 13C) e espectrometria de massas de alta resolução. Todos os compostos sintetizados foram capazes de inibir a AChE seletivamente frente à BChE, em que o composto mais ativo apresentou CI50 = 0,02 µM e seletividade de 337 (BChE CI50/AChE CI50), perfil muito semelhante ao fármaco referência donepezila (AChE CI50 = 0,007 µM e seletividade de 341). Adicionalmente, os compostos mostraram perfil de inibição mista para ambas as colinesterases, o que foi corroborado por análises de docking molecular que demonstraram a interação dos compostos com os sítios catalítico (CAS) e periférico (PAS). |
| publishDate |
2018 |
| dc.date.issued.fl_str_mv |
2018-11-21 |
| dc.date.accessioned.fl_str_mv |
2023-12-22T03:03:31Z |
| dc.date.available.fl_str_mv |
2023-12-22T03:03:31Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
| format |
masterThesis |
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SOUZA, Gabriela Alves de. Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer. 2018. 150 f. Dissertação (Mestrado em Quìmica) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2018. |
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https://rima.ufrrj.br/jspui/handle/20.500.14407/14615 |
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SOUZA, Gabriela Alves de. Síntese de compostos alquilamino-cumarínicos planejados como inibidores da acetilcolinesterase e agregação de placas βamiloides para o tratamento da doença de Alzheimer. 2018. 150 f. Dissertação (Mestrado em Quìmica) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2018. |
| url |
https://rima.ufrrj.br/jspui/handle/20.500.14407/14615 |
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por |
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por |
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Biblioteca Digital de Teses e Dissertações da UFRRJ - Universidade Federal Rural do Rio de Janeiro (UFRRJ) |
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