Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase
| Ano de defesa: | 2024 |
|---|---|
| Autor(a) principal: |
Santos, Mayara Carla dos
 |
| Orientador(a): |
Lacerda, Renata Barbosa
|
| Banca de defesa: |
Lacerda, Renata Barbosa
,
Santos, Claudio Eduardo Rodrigues dos
,
Alves, Marina Amaral
|
| Tipo de documento: | Dissertação |
| Tipo de acesso: | Acesso aberto |
| Idioma: | por |
| Instituição de defesa: |
Universidade Federal Rural do Rio de Janeiro
|
| Programa de Pós-Graduação: |
Programa de Pós-Graduação em Química
|
| Departamento: |
Instituto de Química
|
| País: |
Brasil
|
| Palavras-chave em Português: | |
| Área do conhecimento CNPq: | |
| Link de acesso: | https://rima.ufrrj.br/jspui/handle/20.500.14407/23660 |
Resumo: | A doença de Alzheimer (DA) é uma doença neurodegenerativa progressiva, caracterizada pela deficiência de neurônios colinérgicos intactos. A butirilcolinesterase (BuChE) e a acetilcolinesterase (AChE) são enzimas do sistema nervoso que catalisam a hidrólise da acetilcolina (ACh), diminuindo os níveis do neurotransmissor e finalizando a comunicação entre as células nervosas. A AChE é ainda o principal alvo terapêutico para o tratamento da DA, no entanto estudos sugerem importante papel da BuChE na hidrólise da ACh em estágios mais avançados da DA, sendo os inibidores seletivos de BuChE vislumbrados como potenciais candidatos para o tratamento desta doença. Este trabalho descreve uma nova série de acilguanidinas quinolínicas (59-62A-D; 63-66A-D) planejadas como inibidores seletivos de BuChE. O planejamento estrutural se baseou nas acilguanidinas indólicas e bromopirrólicas descritas previamente por nosso grupo, as quais se mostraram inibidores seletivos de BuChE. Nos novos derivados o farmacóforo acilguanidina foi mantido e, através do bioisosterismo, propomos a troca do heterociclo principal pelo núcleo quinolínico com diferentes padrões de substituição na posição dois do heterociclo central. A síntese dos compostos se baseou na obtenção dos intermediários-chave terc- butil((metiltio)(quinolina-4-carboxamido) metileno) carbamatos (58a-d) para posterior condensação com as aminas de interesse (A-D) e subsequente reação em meio ácido para remoção do grupo de proteção (N-Boc). Foram sintetizados 20 compostos originais, entre acilguanidinas protegidas (59-62-A-D) e desprotegidas (63-66-A-D), caracterizados por RMN1H e RMN13C. As acilguanidinas desprotegidas fenil-quinolínicas (64A-D) foram idendificadas como inibidores seletivos enzima BuChE (CI50 entre 7 e 12 μM). As duas acilguanidinas com menores valores de CI50 para inibição da BuChE (64C-D) foram avaliadas quanto ao seu perfil antioxidante no modelo do DPPH mas não apresentaram atividade na concentração utilizada (100μM). Estudos de ancoramento molecular possibilitaram a compreensão dos possíveis modos de interação dos compostos ativos com a BuChE e a predição in silico das propriedades ADME e druglike sugere que as novas acilguanidinas quinolínicas tem bom perfil farmacocinético. |
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Santos, Mayara Carla dosLacerda, Renata Barbosahttps://orcid.org/0000-0002-6185-3408http://lattes.cnpq.br/2068820144272983Kümmerle, Arthur Eugenhttp://lattes.cnpq.br/5598000938584486Lacerda, Renata Barbosahttps://orcid.org/0000-0002-6185-3408http://lattes.cnpq.br/2068820144272983Santos, Claudio Eduardo Rodrigues doshttps://orcid.org/0000-0003-0129-2802http://lattes.cnpq.br/0890271430013129Alves, Marina Amaralhttps://orcid.org/0000-0002-8188-5554http://lattes.cnpq.br/0945374845574106http://lattes.cnpq.br/21153706152312252025-11-03T16:33:46Z2025-11-03T16:33:46Z2024-04-26SANTOS, Mayara Carla dos. Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase. 2024.133 f. Dissertação (Mestrado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, 2024.https://rima.ufrrj.br/jspui/handle/20.500.14407/23660A doença de Alzheimer (DA) é uma doença neurodegenerativa progressiva, caracterizada pela deficiência de neurônios colinérgicos intactos. A butirilcolinesterase (BuChE) e a acetilcolinesterase (AChE) são enzimas do sistema nervoso que catalisam a hidrólise da acetilcolina (ACh), diminuindo os níveis do neurotransmissor e finalizando a comunicação entre as células nervosas. A AChE é ainda o principal alvo terapêutico para o tratamento da DA, no entanto estudos sugerem importante papel da BuChE na hidrólise da ACh em estágios mais avançados da DA, sendo os inibidores seletivos de BuChE vislumbrados como potenciais candidatos para o tratamento desta doença. Este trabalho descreve uma nova série de acilguanidinas quinolínicas (59-62A-D; 63-66A-D) planejadas como inibidores seletivos de BuChE. O planejamento estrutural se baseou nas acilguanidinas indólicas e bromopirrólicas descritas previamente por nosso grupo, as quais se mostraram inibidores seletivos de BuChE. Nos novos derivados o farmacóforo acilguanidina foi mantido e, através do bioisosterismo, propomos a troca do heterociclo principal pelo núcleo quinolínico com diferentes padrões de substituição na posição dois do heterociclo central. A síntese dos compostos se baseou na obtenção dos intermediários-chave terc- butil((metiltio)(quinolina-4-carboxamido) metileno) carbamatos (58a-d) para posterior condensação com as aminas de interesse (A-D) e subsequente reação em meio ácido para remoção do grupo de proteção (N-Boc). Foram sintetizados 20 compostos originais, entre acilguanidinas protegidas (59-62-A-D) e desprotegidas (63-66-A-D), caracterizados por RMN1H e RMN13C. As acilguanidinas desprotegidas fenil-quinolínicas (64A-D) foram idendificadas como inibidores seletivos enzima BuChE (CI50 entre 7 e 12 μM). As duas acilguanidinas com menores valores de CI50 para inibição da BuChE (64C-D) foram avaliadas quanto ao seu perfil antioxidante no modelo do DPPH mas não apresentaram atividade na concentração utilizada (100μM). Estudos de ancoramento molecular possibilitaram a compreensão dos possíveis modos de interação dos compostos ativos com a BuChE e a predição in silico das propriedades ADME e druglike sugere que as novas acilguanidinas quinolínicas tem bom perfil farmacocinético.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqCoordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESAlzheimer's disease (AD) is a progressive neurodegenerative disease characterized by a deficiency of intact cholinergic neurons. Butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) are nervous system enzymes that catalyze the hydrolysis of acetylcholine (ACh), reducing neurotransmitter levels and ending communication between nerve cells. AChE is still the main therapeutic target for the treatment of AD, however studies suggest an important role for BuChE in the hydrolysis of ACh in more advanced stages of AD, with selective BuChE inhibitors being seen as potential candidates for the treatment of this disease. This work describes a new series of quinolinic acylguanidines (59-62A-D; 63-66A-D) designed as selective inhibitors of BuChE. Structural design was based on the indole and bromopyrrolic acylguanidines previously described by our group, which were shown to be selective inhibitors of BuChE. In the new derivatives, the acylguanidine pharmacophore was maintained and, through bioisosterism, we propose the exchange of the main heterocycle for the quinoline nucleus with different substitution patterns in position two of the central heterocycle. The synthesis of the compounds was based on obtaining the key intermediates tert-butyl((methylthio)(quinoline-4- carboxamido) methylene) carbamates (58a-d) for subsequent condensation with the amines of interest (A-D) and subsequent reaction in an acidic medium to remove the protecting group ( N-Boc). 20 original compounds were synthesized, including protected (59-62-A- D) and free acylguanidines (63-66-A-D), characterized by H1NMR and DEPTQ. The free phenyl-quinoline acylguanidines (64A-D) were identified as selective inhibitors of the BuChE enzyme (IC50 between 7 and 12 μM). The two acylguanidines with the lowest IC50 values for BuChE inhibition (64C-D) were evaluated for their antioxidant profile in the DPPH model, but showed no activity at tested concentration (110μM). Molecular docking studies made it possible to understand the possible modes of interaction of active compounds with BuChE and in silico prediction of ADME and druglike properties suggests that the new quinolinic acylguanidines have a good pharmacokinetic profile.porUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de QuímicaQuímicaQuímicadoença de Alzheimerquinolinasacilguanidinasinibidores de butirilcolinesteraseAlzheimer's diseasequinolinesacylguanidinesbutyrylcholinesterase inhibitors.Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesteraseNovel acyguanidine quinolines designed as selective butyrylcholinesterase inhibitorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisAJANI, O. O.; IYAYE, K. T.; ADEMOSUN, O. T. Recent advances in chemistry and therapeutic potential of functionalized quinoline motifs - a review. RSC AdvancesRoyal Society of Chemistry, , 24 jun. 2022. 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Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. 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| dc.title.pt_BR.fl_str_mv |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| dc.title.alternative.en.fl_str_mv |
Novel acyguanidine quinolines designed as selective butyrylcholinesterase inhibitors |
| title |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| spellingShingle |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase Santos, Mayara Carla dos Química Química doença de Alzheimer quinolinas acilguanidinas inibidores de butirilcolinesterase Alzheimer's disease quinolines acylguanidines butyrylcholinesterase inhibitors. |
| title_short |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| title_full |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| title_fullStr |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| title_full_unstemmed |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| title_sort |
Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase |
| author |
Santos, Mayara Carla dos |
| author_facet |
Santos, Mayara Carla dos |
| author_role |
author |
| dc.contributor.author.fl_str_mv |
Santos, Mayara Carla dos |
| dc.contributor.advisor1.fl_str_mv |
Lacerda, Renata Barbosa |
| dc.contributor.advisor1ID.fl_str_mv |
https://orcid.org/0000-0002-6185-3408 |
| dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/2068820144272983 |
| dc.contributor.advisor-co1.fl_str_mv |
Kümmerle, Arthur Eugen |
| dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/5598000938584486 |
| dc.contributor.referee1.fl_str_mv |
Lacerda, Renata Barbosa |
| dc.contributor.referee1ID.fl_str_mv |
https://orcid.org/0000-0002-6185-3408 |
| dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/2068820144272983 |
| dc.contributor.referee2.fl_str_mv |
Santos, Claudio Eduardo Rodrigues dos |
| dc.contributor.referee2ID.fl_str_mv |
https://orcid.org/0000-0003-0129-2802 |
| dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/0890271430013129 |
| dc.contributor.referee3.fl_str_mv |
Alves, Marina Amaral |
| dc.contributor.referee3ID.fl_str_mv |
https://orcid.org/0000-0002-8188-5554 |
| dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/0945374845574106 |
| dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/2115370615231225 |
| contributor_str_mv |
Lacerda, Renata Barbosa Kümmerle, Arthur Eugen Lacerda, Renata Barbosa Santos, Claudio Eduardo Rodrigues dos Alves, Marina Amaral |
| dc.subject.cnpq.fl_str_mv |
Química Química |
| topic |
Química Química doença de Alzheimer quinolinas acilguanidinas inibidores de butirilcolinesterase Alzheimer's disease quinolines acylguanidines butyrylcholinesterase inhibitors. |
| dc.subject.por.fl_str_mv |
doença de Alzheimer quinolinas acilguanidinas inibidores de butirilcolinesterase Alzheimer's disease quinolines acylguanidines butyrylcholinesterase inhibitors. |
| description |
A doença de Alzheimer (DA) é uma doença neurodegenerativa progressiva, caracterizada pela deficiência de neurônios colinérgicos intactos. A butirilcolinesterase (BuChE) e a acetilcolinesterase (AChE) são enzimas do sistema nervoso que catalisam a hidrólise da acetilcolina (ACh), diminuindo os níveis do neurotransmissor e finalizando a comunicação entre as células nervosas. A AChE é ainda o principal alvo terapêutico para o tratamento da DA, no entanto estudos sugerem importante papel da BuChE na hidrólise da ACh em estágios mais avançados da DA, sendo os inibidores seletivos de BuChE vislumbrados como potenciais candidatos para o tratamento desta doença. Este trabalho descreve uma nova série de acilguanidinas quinolínicas (59-62A-D; 63-66A-D) planejadas como inibidores seletivos de BuChE. O planejamento estrutural se baseou nas acilguanidinas indólicas e bromopirrólicas descritas previamente por nosso grupo, as quais se mostraram inibidores seletivos de BuChE. Nos novos derivados o farmacóforo acilguanidina foi mantido e, através do bioisosterismo, propomos a troca do heterociclo principal pelo núcleo quinolínico com diferentes padrões de substituição na posição dois do heterociclo central. A síntese dos compostos se baseou na obtenção dos intermediários-chave terc- butil((metiltio)(quinolina-4-carboxamido) metileno) carbamatos (58a-d) para posterior condensação com as aminas de interesse (A-D) e subsequente reação em meio ácido para remoção do grupo de proteção (N-Boc). Foram sintetizados 20 compostos originais, entre acilguanidinas protegidas (59-62-A-D) e desprotegidas (63-66-A-D), caracterizados por RMN1H e RMN13C. As acilguanidinas desprotegidas fenil-quinolínicas (64A-D) foram idendificadas como inibidores seletivos enzima BuChE (CI50 entre 7 e 12 μM). As duas acilguanidinas com menores valores de CI50 para inibição da BuChE (64C-D) foram avaliadas quanto ao seu perfil antioxidante no modelo do DPPH mas não apresentaram atividade na concentração utilizada (100μM). Estudos de ancoramento molecular possibilitaram a compreensão dos possíveis modos de interação dos compostos ativos com a BuChE e a predição in silico das propriedades ADME e druglike sugere que as novas acilguanidinas quinolínicas tem bom perfil farmacocinético. |
| publishDate |
2024 |
| dc.date.issued.fl_str_mv |
2024-04-26 |
| dc.date.accessioned.fl_str_mv |
2025-11-03T16:33:46Z |
| dc.date.available.fl_str_mv |
2025-11-03T16:33:46Z |
| 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 |
SANTOS, Mayara Carla dos. Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase. 2024.133 f. Dissertação (Mestrado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, 2024. |
| dc.identifier.uri.fl_str_mv |
https://rima.ufrrj.br/jspui/handle/20.500.14407/23660 |
| identifier_str_mv |
SANTOS, Mayara Carla dos. Novas quinolinas acilguanidínicas planejadas como inibidores seletivos de butirilcolinesterase. 2024.133 f. Dissertação (Mestrado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, 2024. |
| url |
https://rima.ufrrj.br/jspui/handle/20.500.14407/23660 |
| dc.language.iso.fl_str_mv |
por |
| language |
por |
| dc.relation.references.pt_BR.fl_str_mv |
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