Estudos quimiométricos das relações estrutura atividade de compostos com ação dual no receptor H3 e colinesterases: potenciais agentes pró-cognitivos
Data
2023-06-26
Autores
Arruda, Maria Cecília Cheganças 
Orientadores
Fernandes, João Paulo dos Santos
Tipo
Trabalho de conclusão de curso
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A relação entre as vias colinérgicas e histaminérgicas nos processos cognitivos
impulsiona a busca por fármacos capazes de atuar em ambos os alvos para o
tratamento de doenças relacionadas à demência. Neste cenário, o presente trabalho
teve como objetivo estudar as relações entre estrutura química e atividade
farmacológica de compostos com atividade em H3R e ChEs. Dois grupos distintos de
compostos piperidínicos substituídos nas posições 3 e 4 do anel fenoxila e outros
análogos foram estudados em relação às suas características estruturais, utilizando
metodologias quimiométricas, para analisar suas propriedades físicoquímicas e
relacionálas com suas propriedades farmacológicas no receptor H3 de histamina e
nas colinesterases. Para isso, uma série de descritores de lipofilicidade, propriedades
topológicas e estéricas e outros foram calculados, e utilizados em estudos de análise
de componentes principais (PCA) e análise hierárquica de agrupamentos (HCA). Os
resultados da análise do primeiro grupo indicaram moléculas volumosas e com
espaçante menor entre a região lipofílica e básica tem alta afinidade em H3R e as
moléculas que melhor atuam nas ChEs são menos volumosas e tem maior espaçante
entre as duas regiões, revelando a necessidade de analisar mais descritores para
planejar moléculas com ação dual entre os alvos. Enquanto a análise do segundo
grupo revelou que moléculas com características mais lipofílicas, volumosas, estáveis
e com um espaçante longo entre a região lipofílica e básica tem alta afinidade em H3R
e alta atividade inibitória a BuChE, permitindo uma perspectiva multialvo sob esses
alvos. Os resultados revelaram importantes informações estruturais que auxiliarão no
planejamento de moléculas com ação dual, aumentando seu potencial como agentes
prócognitivos.
The relationship between cholinergic and histaminergic pathways in cognitive processes drives the search for drugs capable of acting on both targets for the treatment of dementiarelated diseases. In this scenario, the present work aimed to study the relationships between chemical structure and pharmacological activity of compounds with activity in H3R and ChEs. Two distinct groups of piperidine compounds substituted at positions 3 and 4 of the phenoxyl ring and other analogues were studied in relation to their structural characteristics, using chemometric methodologies, to analyze their physicalchemical properties and relate them to their pharmacological properties in the H3 receptor of histamine and cholinesterases. For this, a series of descriptors of lipophilicity, topological and steric properties and others were calculated, and used in studies of principal component analysis (PCA) and hierarchical cluster analysis (HCA). The results of the analysis of the first group indicated that bulky molecules with a smaller linker between the lipophilic and basic regions have high affinity for H3R and the molecules that best act on ChEs are less bulky and have a larger linker between the two regions, revealing the need to analyze more descriptors to design molecules with dual action between targets. While the analysis of the second group revealed that molecules with more lipophilic, bulky, stable characteristics and with a long linker between the lipophilic and basic regions have high affinity for H3R and high inhibitory activity for BuChE, allowing a multitarget perspective on these targets. The results revealed important structural information that will help in the design of molecules with dual action, increasing their potential as procognitive agents.
The relationship between cholinergic and histaminergic pathways in cognitive processes drives the search for drugs capable of acting on both targets for the treatment of dementiarelated diseases. In this scenario, the present work aimed to study the relationships between chemical structure and pharmacological activity of compounds with activity in H3R and ChEs. Two distinct groups of piperidine compounds substituted at positions 3 and 4 of the phenoxyl ring and other analogues were studied in relation to their structural characteristics, using chemometric methodologies, to analyze their physicalchemical properties and relate them to their pharmacological properties in the H3 receptor of histamine and cholinesterases. For this, a series of descriptors of lipophilicity, topological and steric properties and others were calculated, and used in studies of principal component analysis (PCA) and hierarchical cluster analysis (HCA). The results of the analysis of the first group indicated that bulky molecules with a smaller linker between the lipophilic and basic regions have high affinity for H3R and the molecules that best act on ChEs are less bulky and have a larger linker between the two regions, revealing the need to analyze more descriptors to design molecules with dual action between targets. While the analysis of the second group revealed that molecules with more lipophilic, bulky, stable characteristics and with a long linker between the lipophilic and basic regions have high affinity for H3R and high inhibitory activity for BuChE, allowing a multitarget perspective on these targets. The results revealed important structural information that will help in the design of molecules with dual action, increasing their potential as procognitive agents.