Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multialvo
Data
2021-07-01
Orientadores
Fernandes, João Paulo dos Santos 
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A maioria das desordens neurológicas estão associadas com certo declínio cognitivo. Os mecanismos que regem os processos de memória e aprendizado são complexos e comumente explorados na busca por alvos para uma melhor terapia farmacológica. É proposto que esses tipos de condições são melhores tratadas através da abordagem multialvo, i.e. por interferir em mais de um alvo simultaneamente. O papel dos sistemas histaminérgico, colinérgico e dopaminérgico, juntamente com o processo inflamatório, é amplamente conhecido, e assim esses sistemas podem ser considerados promissores para se alcançar novos fármacos. A esse respeito, compostos da série LINS01 (diidrobenzofuranil-piperazinas) foram sintetizados e avaliados em ensaios farmacológicos in vitro (afinidade e atividade funcional) nos receptores H3, H4, D2 e D3 e atividade inibitória frente a AChE. Os compostos foram preparados através de metodologias desenvolvidas pelo grupo, envolvendo os fenóis como material de partida para reações de alilação, rearranjo termal, ciclização e alquilação. Foram sintetizados onze compostos finais e os rendimentos variaram de 22 a 70%. Os ensaios de afinidade demonstraram que os compostos LINS01 apresentaram preferência para o H3R e D3R em relação ao H4R e D2R. Dentre eles, destacam-se o 1g (LINS01022; H3R pKi 8,2), 1h (LINS01023; H3R pKi 7,8), 1i (LINS01024; H3R pKi 8,4) e LINS01004 (D3R Ki 5,5 μM). Foi demonstrado que substituições na porção N-piperazina podem levar ao aumento da afinidade e seletividade, sendo os compostos N-alilados os mais promissores para ação multialvo. Estudos de modelagem molecular foram realizados e os resutados sugeriram que substituintes volumosos ocupam um bolso hidrofóbico e o grupo alila forma uma interação favorável com o H3R, aumentando sua seletividade. Além disso, o ensaio de BRET indicou que os compostos possuem atividade antagonista H3R. O modelo estrutural dos compostos LINS01 demonstrou-se promissor para obtenção de ligantes de receptores histaminérgicos e dopaminérgicos. Por fim, o ensaio in vivo, sugeriu que os compostos LINS01 avaliados, atuam por antagonismo no H3R e não prejudicam a memória de esquiva discriminativa.
Most neurological disorders are associated with cognitive decline. The mechanisms that control memory and learning processes are complex and are commonly explored in the search for targets for better pharmacological therapy. It is proposed that these types of conditions are best treated through the multi-target approach, i.e. by interfering with more than one target simultaneously. The role of the histaminergic, cholinergic and dopaminergic systems, together with the inflammatory process, is widely known, and so these systems can be considered promising to design of new drugs. In this regard, compounds from the LINS01 series (dihydrobenzofuranylpiperazines) were synthesized and evaluated in in vitro pharmacological assays (affinity and functional activity) at H3, H4, D2 and D3 receptors and inhibitory activity against AChE. The compounds were prepared using methodologies developed by the group, involving phenols as starting material for reactions of allylation, thermal rearrangement, cyclization and alkylation. Eleven final compounds were synthesized and yields ranged from 22 to 70%. Affinity assays showed that LINS01 compounds had preference for H3R and D3R over H4R and D2R. Among them, we highlight the 1g (LINS01022; H3R pKi 8.2), 1h (LINS01023; H3R pKi 7.8), 1i (LINS01024; H3R pKi 8.4) and LINS01004 (D3R Ki 5.5 µM). Our data demonstrated that substitutions in the N-piperazine portion can lead to increased affinity and selectivity, with N-allylated compounds being the most promising for multi-target action. Molecular docking studies were carried out and the results suggested that bulky substituents occupy a hydrophobic pocket and the ally group forms a favorable interaction with H3R, increasing its selectivity. In addition, BRET assay indicated that the compounds have H3R antagonist activity. The structural model of the LINS01 compounds showed to be promising for obtaining histaminergic and dopaminergic receptor ligands. Finally, with the in vivo experiment, it was suggested that the LINS01 compounds evaluated, act by antagonism in H3R and do not impair discriminative avoidance memory.
Most neurological disorders are associated with cognitive decline. The mechanisms that control memory and learning processes are complex and are commonly explored in the search for targets for better pharmacological therapy. It is proposed that these types of conditions are best treated through the multi-target approach, i.e. by interfering with more than one target simultaneously. The role of the histaminergic, cholinergic and dopaminergic systems, together with the inflammatory process, is widely known, and so these systems can be considered promising to design of new drugs. In this regard, compounds from the LINS01 series (dihydrobenzofuranylpiperazines) were synthesized and evaluated in in vitro pharmacological assays (affinity and functional activity) at H3, H4, D2 and D3 receptors and inhibitory activity against AChE. The compounds were prepared using methodologies developed by the group, involving phenols as starting material for reactions of allylation, thermal rearrangement, cyclization and alkylation. Eleven final compounds were synthesized and yields ranged from 22 to 70%. Affinity assays showed that LINS01 compounds had preference for H3R and D3R over H4R and D2R. Among them, we highlight the 1g (LINS01022; H3R pKi 8.2), 1h (LINS01023; H3R pKi 7.8), 1i (LINS01024; H3R pKi 8.4) and LINS01004 (D3R Ki 5.5 µM). Our data demonstrated that substitutions in the N-piperazine portion can lead to increased affinity and selectivity, with N-allylated compounds being the most promising for multi-target action. Molecular docking studies were carried out and the results suggested that bulky substituents occupy a hydrophobic pocket and the ally group forms a favorable interaction with H3R, increasing its selectivity. In addition, BRET assay indicated that the compounds have H3R antagonist activity. The structural model of the LINS01 compounds showed to be promising for obtaining histaminergic and dopaminergic receptor ligands. Finally, with the in vivo experiment, it was suggested that the LINS01 compounds evaluated, act by antagonism in H3R and do not impair discriminative avoidance memory.
Descrição
Citação
CORRÊA, Michelle Fidelis. Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multiavo. São Paulo, 2021. 230 f. Tese (Doutorado em Medicina Translacional) – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2021.