Planejamento e síntese de uma série de derivados aril-alquilpiperazínicos com potencial atividade anticolinesterásica em uma abordagem multialvo
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Data
2021-02-12
Autores
Lopes, Flávia Barrio [UNIFESP]
Orientadores
Fernandes, João Paulo dos Santos [UNIFESP]
Tipo
Trabalho de conclusão de curso de graduação
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Resumo
O envolvimento de vias colinérgicas com processos cognitivos, principalmente associados ao aprendizado e formação da memória, tem feito com que a busca por fármacos com a capacidade de atuar nessas vias seja promissora para o tratamento de doenças relacionadas à demência, como, por exemplo, a Doença de Alzheimer. Nesse sentido, este trabalho objetivou planejar, sintetizar e avaliar uma série de derivados aril-alquilpiperazínicos, com variações no anel aromático, na cadeia alquílica e no nitrogênio terminal, como agentes anticolinesterásicos. O planejamento da série levou à construção de compostos com grupos funcionais ureída e amida, contendo como grupamentos básicos a 1-fenilpiperazina e a 1-(4-piridil)piperazina. Devido à semelhança dos ligantes planejados com antagonistas de receptores H3 de histamina, a série também pode ser vista sob uma perspectiva multialvo. Foram obtidos quatro compostos finais, com rendimentos que variaram de 10 % a 67 %. Estes foram testados quanto à capacidade de inibição da acetilcolinesterase de Electrophorus electricus em duas concentrações fixas, 1 μM e 100 μM, e o composto 5d foi o mais eficaz em inibir a atividade da enzima (48 % de inibição a 100 μM). Tais resultados, quando avaliados de acordo com as características estruturais individuais, contribuem com informações de REA importantes para otimizar a atividade de novos compostos, e futuros estudos com outros derivados que estão em andamento.
The involvement of cholinergic pathways with cognitive processes, mainly associated with learning and memory formation, has made the search for drugs with the ability to act in these pathways promising for the treatment of diseases related to dementia, such as, for example, Alzheimer's Disease. In this regard, this work aimed to design, synthesize and evaluate a set of aryl-alkylpiperazine derivatives, with variations in the aromatic ring, the alkyl chain and the terminal nitrogen, as anticholinesterase agents. The design of this series led to the construction of compounds with ureide and amide functional groups, and containing 1-phenylpiperazine and 1-(4-pyridyl)piperazine as basic groups. Due to the similarity of the designed ligands with histamine H3 receptors antagonists, the series can also be seen from a multi-target perspective. Four final compounds were obtained, with yields ranging from 67 % to 10 %. These were tested for ability to inhibit Electrophorus electricus acetylcholinesterase in two predetermined concentrations, 100 μM and 1 μM, being the compound 5d the most effective in inhibiting the enzyme (48% at 100 μM). Such results added important SAR information to optimize the activity of new compounds, and studies with novel compounds are in progress.
The involvement of cholinergic pathways with cognitive processes, mainly associated with learning and memory formation, has made the search for drugs with the ability to act in these pathways promising for the treatment of diseases related to dementia, such as, for example, Alzheimer's Disease. In this regard, this work aimed to design, synthesize and evaluate a set of aryl-alkylpiperazine derivatives, with variations in the aromatic ring, the alkyl chain and the terminal nitrogen, as anticholinesterase agents. The design of this series led to the construction of compounds with ureide and amide functional groups, and containing 1-phenylpiperazine and 1-(4-pyridyl)piperazine as basic groups. Due to the similarity of the designed ligands with histamine H3 receptors antagonists, the series can also be seen from a multi-target perspective. Four final compounds were obtained, with yields ranging from 67 % to 10 %. These were tested for ability to inhibit Electrophorus electricus acetylcholinesterase in two predetermined concentrations, 100 μM and 1 μM, being the compound 5d the most effective in inhibiting the enzyme (48% at 100 μM). Such results added important SAR information to optimize the activity of new compounds, and studies with novel compounds are in progress.