Síntese e avaliação da atividade de aril-alquilamido-piperazinas como ligantes duais de receptores H3 e colinesterases
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Data
2024-01-26
Autores
Andrade, Isabela Will de
Orientadores
Fernandes, João Paulo dos Santos [UNIFESP]
Tipo
Dissertação de mestrado
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Resumo
Grande parte das doenças neurológicas que acarretam declínio cognitivo, envolve um desbalanço de neurotransmissores no Sistema Nervoso Central (SNC). Desta forma, pelo fato dos sistemas colinérgico e histaminérgico estarem intimamente relacionados com os processos cognitivos, a interação entre alvos presentes nesses sistemas pode gerar considerável melhora na cognição. Em vista disso, o planejamento e desenvolvimento de um único fármaco capaz de agir em mais de um alvo de interesse seria uma estratégia viável para o tratamento do déficit cognitivo presente nessas doenças neurológicas. Portanto, na busca por novos agentes duais anti-colinesterásicos (ChE) e antagonistas/ agonistas inversos dos receptores H3 (H3R), um conjunto de aril-alquilamido-piperazinas foi planejado e sintetizado com variações dos substituintes da região aromática e do grupo básico. Estes compostos foram preparados a partir de fenóis, que foram alquilados com cloroalquilésteres, hidrolizados e então usados para preparar as amidas finais com substituintes piperazínicos. Onze compostos foram preparados, dos quais 9 foram testados quanto à capacidade de inibição nas colinesterases a 100 μM, sendo que os mais promissores tiveram o seu IC50 determinado. Como resultado, os compostos geraram porcentagens de inibição que variaram de 16-65% na butirilcolinesterase (BuCHE) e 40-59% na acetilcolinesterase (AChE), sendo que o composto 6a apresentou a melhor capacidade de inibição na BuCHE (IC50 57,75 μM), e alguma atividade na AChE (59% de inibição a 100 μM). Apenas os compostos 6a e 6b foram testados quanto à inibição do H3R (1 μM), apresentando 58% e 50% de taxas de inibição, respectivamente. Em suma, os compostos precisam ser aprimorados futuramente para atingir melhores resultados como inibidores das ChEs e afinidade nos H3Rs.
Most neurological diseases that lead to cognitive decline involve an imbalance of neurotransmitters in the Central Nervous System (CNS). Thus, since the cholinergic and histaminergic systems are closely related in cognitive processes, the interaction with these targets present in these systems can generate considerable improvement in cognition. In view of this, the design and development of a single drug, known as multitarget approach, capable of acting in more than one target of interest would be a viable strategy for the treatment of the cognitive deficit present in these neurological diseases. Therefore, in the search for novel dual anti-cholinesterase (ChE) and histamine H3 receptor (H3R) antagonist agents, a set of aryl-alkylamido-piperazines were designed and synthesized with variations on the substituents in the aromatic moiety and in the basic group. The compounds were prepared from phenols, which were alkylated with cloroalkyl esters, hydrolyzed and then, used to prepare the final amides with piperazines substituints. 11 compounds were prepared, in which 9 were tested for their capacity to inhibit cholinesterases at 100 μM, with the most promising having their IC50 determined. As a result, the compounds generated inhibition percentages that ranged from 16-65% on butyrylcholinesterase (BuCHE) and 40-59% on acetylcholinesterase (AChE), in which compound 6a showed the best inhibition capacity on BuChE (IC50 57.75 μM) and some activity on AChE (59% of inhibition at 100 μM). Only compounds 6a and 6b were tested for inhibition on H3R (1 μM), showing 58% and 50% of inhibition rates, respectively. In short, the compounds need to be improved in the future to achieve better results as ChEs inhibitors and affinity on H3R.
Most neurological diseases that lead to cognitive decline involve an imbalance of neurotransmitters in the Central Nervous System (CNS). Thus, since the cholinergic and histaminergic systems are closely related in cognitive processes, the interaction with these targets present in these systems can generate considerable improvement in cognition. In view of this, the design and development of a single drug, known as multitarget approach, capable of acting in more than one target of interest would be a viable strategy for the treatment of the cognitive deficit present in these neurological diseases. Therefore, in the search for novel dual anti-cholinesterase (ChE) and histamine H3 receptor (H3R) antagonist agents, a set of aryl-alkylamido-piperazines were designed and synthesized with variations on the substituents in the aromatic moiety and in the basic group. The compounds were prepared from phenols, which were alkylated with cloroalkyl esters, hydrolyzed and then, used to prepare the final amides with piperazines substituints. 11 compounds were prepared, in which 9 were tested for their capacity to inhibit cholinesterases at 100 μM, with the most promising having their IC50 determined. As a result, the compounds generated inhibition percentages that ranged from 16-65% on butyrylcholinesterase (BuCHE) and 40-59% on acetylcholinesterase (AChE), in which compound 6a showed the best inhibition capacity on BuChE (IC50 57.75 μM) and some activity on AChE (59% of inhibition at 100 μM). Only compounds 6a and 6b were tested for inhibition on H3R (1 μM), showing 58% and 50% of inhibition rates, respectively. In short, the compounds need to be improved in the future to achieve better results as ChEs inhibitors and affinity on H3R.