Potenciais agentes multialvo para o tratamento de neurodegenerações: inibidores duais H3R/ChEs com propriedades quelantes associadas
Arquivos
Data
2023-05-26
Autores
Lopes, Flávia Barrio 
Orientadores
Fernandes, João Paulo dos Santos
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Doenças neurodegenerativas são caracterizadas pela morte neuronal progressiva, que pode levar à perda de funções, incluindo aquelas relacionadas à cognição. Diversos fenômenos estão envolvidos com a perda neuronal, mas o estresse oxidativo é um dos mais evidentes. Considerando o papel que a histamina e a acetilcolina têm nos processos cognitivos e a influência de metais di- e trivalentes em eventos relacionados ao estresse oxidativo, moléculas capazes de interferir na transmissão histaminérgica e colinérgica, aliados ao potencial antioxidante de agentes quelantes (chamadas moléculas multialvo), podem representar um avanço no tratamento dessas doenças. Assim, uma série de arilalquilaminas foi planejada com variações na região (hetero)aromática, na cadeia alquílica e no nitrogênio terminal. Os compostos foram obtidos a partir de reações orgânicas clássicas, que conduziram a rendimentos satisfatórios, permitindo a caracterização e análise biológica. Dezoito compostos foram testados quanto à capacidade de inibição da acetilcolinesterase de enguia (eeAChE) e da butirilcolinesterase equina (eqBuChE), utilizando a metodologia de Ellman. Dentre estes, destacam-se os compostos 5h (IC50 AChE 13,21 μM e BuChE 17,86 μM) e 5k (IC50 AChE 43,69 μM e BuChE 11,73 μM), que apresentaram as maiores potências da série. O composto 5i também se destacou pela seletividade em AChE (IC50 AChE 27,26 μM). Dezessete compostos foram avaliados quanto à capacidade em coordenar com os metais Fe2+, Fe3+, Cu2+ e Zn2+ através de ensaio espectrofotométrico. As análises apontaram que os compostos 3e, 5a, 5f e 6a apresentaram propriedades quelantes de Cu2+ e o composto 5j demonstrou complexar com os íons Fe3+ e Cu2+. Os resultados obtidos sugerem que variações na região aromática podem afetar tanto o perfil de seletividade entre as duas enzimas, quanto à capacidade em formar complexos com os metais estudados. Modificações no grupo amino básico influenciaram principalmente a potência em inibir ambas as enzimas e podem influenciar a afinidade desses compostos como ligantes de H3R. Em suma, o composto 6a pode ser considerado um ligante dual H3R/ChEs e quelante de Cu2+, promissor como agente multialvo e como protótipo para o desenvolvimento de ligantes multialvo aprimorados.
Neurodegenerative diseases are characterized by progressive neuronal death, which can lead to function deficits, including those related to cognition. Several phenomena are involved with neuronal death, however oxidative stress is one of the most evident. Considering the role that histamine and acetylcholine play in cognitive process and the influence of di- and trivalent metals on events related to oxidative stress, molecules capable of interfering with histaminergic and cholinergic transmission, allied to the antioxidant potential of chelating agents (named multitarget molecules), can represent a breakthrough in the treatment of these diseases. Therefore, a set of arylalkylamines was designed with variations in the (hetero)aromatic moiety, in the alkyl chain and in the terminal nitrogen. The compounds were synthesized from classical organic reactions, which led to satisfactory yields, allowing their characterization and biological analysis. Eighteen compounds were screened for their ability to inhibit eel acetylcholinesterase (eeAChE) and equine butyrylcholinesterase (eqBuChE), using the Ellman’s method. Among these, compounds 5h (IC50 AChE 13.21 μM and BuChE 17.86 μM) and 5k (IC50 AChE 43.69 μM and BuChE 11.73 μM) should be highlighted, which presented the highest potencies in the series. Compound 5i was also noteworthy for its selectivity on AChE (IC50 AChE 27.26 μM). Seventeen compounds were evaluated for their ability to coordinate with Fe2+, Fe3+, Cu2+ and Zn2+ metals through spectrophotometric assay. The analyzes indicated that 3e, 5a, 5f and 6a compounds had Cu2+ chelating properties and the compound 5j demonstrated to complex with Fe3+ e Cu2+ ions. The results obtained suggest that variations in the aromatic region can affect both the selectivity profile and the ability to form complexes with the studied metals. Modifications in the basic amino moiety mainly influenced the inhibitory potency in both enzymes and may influence the affinity of these compounds as H3R ligands. Thus, compound 6a can be considered a dual H3R/ChEs ligand and Cu2+ chelator, promising as a multitarget agent and as a prototype for the designing of improved multitarget ligands.
Neurodegenerative diseases are characterized by progressive neuronal death, which can lead to function deficits, including those related to cognition. Several phenomena are involved with neuronal death, however oxidative stress is one of the most evident. Considering the role that histamine and acetylcholine play in cognitive process and the influence of di- and trivalent metals on events related to oxidative stress, molecules capable of interfering with histaminergic and cholinergic transmission, allied to the antioxidant potential of chelating agents (named multitarget molecules), can represent a breakthrough in the treatment of these diseases. Therefore, a set of arylalkylamines was designed with variations in the (hetero)aromatic moiety, in the alkyl chain and in the terminal nitrogen. The compounds were synthesized from classical organic reactions, which led to satisfactory yields, allowing their characterization and biological analysis. Eighteen compounds were screened for their ability to inhibit eel acetylcholinesterase (eeAChE) and equine butyrylcholinesterase (eqBuChE), using the Ellman’s method. Among these, compounds 5h (IC50 AChE 13.21 μM and BuChE 17.86 μM) and 5k (IC50 AChE 43.69 μM and BuChE 11.73 μM) should be highlighted, which presented the highest potencies in the series. Compound 5i was also noteworthy for its selectivity on AChE (IC50 AChE 27.26 μM). Seventeen compounds were evaluated for their ability to coordinate with Fe2+, Fe3+, Cu2+ and Zn2+ metals through spectrophotometric assay. The analyzes indicated that 3e, 5a, 5f and 6a compounds had Cu2+ chelating properties and the compound 5j demonstrated to complex with Fe3+ e Cu2+ ions. The results obtained suggest that variations in the aromatic region can affect both the selectivity profile and the ability to form complexes with the studied metals. Modifications in the basic amino moiety mainly influenced the inhibitory potency in both enzymes and may influence the affinity of these compounds as H3R ligands. Thus, compound 6a can be considered a dual H3R/ChEs ligand and Cu2+ chelator, promising as a multitarget agent and as a prototype for the designing of improved multitarget ligands.