Estudos computacionais e sintéticos visando o planejamento racional de novos agentes anticolinesterásicos
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Data
2010-08-13
Autores
Danuello, Amanda Coelho [UNESP]
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O presente trabalho teve como objetivo o planejamento e síntese de novas substâncias inibidoras da acetilcolinesterase, enzima cuja modulação está associada ao tratamento de diversas patologias, entre elas a doença de Alzheimer. Para isto foi utilizada a técnica de docking molecular visando o reconhecimento dos sítios de interação da enzima que possibilitaram a modelagem de novos compostos híbridos. O modelo de docking foi criado utilizando a enzima de Torpedo californica, muito semelhante à acetilcolinesterase humana, complexada com a tacrina, donepezil e (–)-huperzina A que foi validado por cross-docking. Em seguida, a (–)-3-O-acetil-espectalina (32), (–)-3-O-acetil-cassina (36) e derivados virtualmente planejados foram ancorados na enzima e a partir de sobreposições destes alcalóides com os inibidores de acetilcolinesterase comerciais foram planejados diversos híbridos que apresentaram interações mais efetivas com a proteína que os modelos originais. Além disto, foram realizados estudos sobre o modo de inibição de 32, que corroboraram os resultados obtidos in vivo, apresentando inibição não-competitiva. A análise por docking e dinâmica molecular sugeriu que 32 e 36 apresentam diferentes interações com a enzima, sendo 36 potencialmente mais ativo que 32. O híbrido planejado por docking que apresentou melhor interação com a AChE, além de maior viabilidade sintética foi selecionado e por análise retrossintética foram escolhidas a 3-hidroxi-2-hidrometil-piridina (38) e a 4-bromoquinolina (42) como materiais de partida para uma rota convergente. Os estudos sintéticos levaram a obtenção de intermediários piridínicos sendo que numa das etapas da rota proposta, onde o objetivo era a proteção seletiva da hidroxila piridínica de 38, foi observada a proteção da hidroxila metil-piridínica o que sugere a migração dos grupos acetil...
The goal of this research deals with the design and synthesis of new acetylcholinesterase inhibitor molecules. This enzyme is associated to the treatment of several pathologies including Alzheimer’s disease and thus the importance of studying molecules that may interact with it. To fulfill this task we used molecular docking aiming to recognize the enzyme’s interaction sites allowing us to design new hybrid compounds. The docking model was created using Torpedo californica’s enzyme, very similar to human acetylcholinesterase, complexed with tacrine, donepezil and (–)-huperzine A, all validated by cross-docking. Furthermore, (–)-3-O-acetyl-espectaline (32), (–)-3-O-acetyl-cassine (36) and virtually designed derivatives, were docked into the enzyme through geometric comparisons of known commercially available acetylcholinesterase inhibitors, allowing us to produce a series of enzyme effective molecular hybrids when compared to the original ones. Additionally, we studied the inhibition mode of action of 32 that confirmed the in vivo results showing a non-competitive inhibition. Docking and molecular dynamics of 32 and 36 revealed that they showed different enzyme interactions and that the latter compound was potentially more active than 32. The hybrid molecule planned by docking that showed a better interaction with AChE and, with the best synthetic viability was selected showing 3-hydroxy-2-hydromethyl-pyridine (38) and 4-bromoquinoline (42) as the starting materials of a convergent route. The synthesis studies lead us to the production of pyridine intermediaries and, in one of the stages where the main goal was the selective protection of a pyridine hydroxyl group; we observed instead, the protection of the methyl pyridine hydroxyl moiety suggesting the migration of the acetyl and benzoyl groups. We used several coupling methods for the pyridine and quinoline nuclei... (Complete abstract click electronic access below)
The goal of this research deals with the design and synthesis of new acetylcholinesterase inhibitor molecules. This enzyme is associated to the treatment of several pathologies including Alzheimer’s disease and thus the importance of studying molecules that may interact with it. To fulfill this task we used molecular docking aiming to recognize the enzyme’s interaction sites allowing us to design new hybrid compounds. The docking model was created using Torpedo californica’s enzyme, very similar to human acetylcholinesterase, complexed with tacrine, donepezil and (–)-huperzine A, all validated by cross-docking. Furthermore, (–)-3-O-acetyl-espectaline (32), (–)-3-O-acetyl-cassine (36) and virtually designed derivatives, were docked into the enzyme through geometric comparisons of known commercially available acetylcholinesterase inhibitors, allowing us to produce a series of enzyme effective molecular hybrids when compared to the original ones. Additionally, we studied the inhibition mode of action of 32 that confirmed the in vivo results showing a non-competitive inhibition. Docking and molecular dynamics of 32 and 36 revealed that they showed different enzyme interactions and that the latter compound was potentially more active than 32. The hybrid molecule planned by docking that showed a better interaction with AChE and, with the best synthetic viability was selected showing 3-hydroxy-2-hydromethyl-pyridine (38) and 4-bromoquinoline (42) as the starting materials of a convergent route. The synthesis studies lead us to the production of pyridine intermediaries and, in one of the stages where the main goal was the selective protection of a pyridine hydroxyl group; we observed instead, the protection of the methyl pyridine hydroxyl moiety suggesting the migration of the acetyl and benzoyl groups. We used several coupling methods for the pyridine and quinoline nuclei... (Complete abstract click electronic access below)
Descrição
Palavras-chave
Química farmacêutica, Molecular hybridization
Como citar
DANUELLO, Amanda Coelho. Estudos computacionais e sintéticos visando o planejamento racional de novos agentes anticolinesterásicos. 2010. 165 f. Tese (doutorado) - Universidade Estadual Paulista Júlio de Mesquita Filho, Instituto de Química de Araraquara, 2010.