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| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Nadur, Nathalia Fonseca | - |
| dc.date.accessioned | 2025-10-03T17:11:07Z | - |
| dc.date.available | 2025-10-03T17:11:07Z | - |
| dc.date.issued | 2025-07-10 | - |
| dc.identifier.citation | NADUR, Nathalia Fonseca. Otimização Estrutural de 7-((piperidin-1-il)alcoxi)-cumarinas: Homologação e Construção de Heterociclos Miméticos Visando o Desenvolvimento de Novos Inibidores Mistos de Colinesterases. 2025. 288 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2025. | pt_BR |
| dc.identifier.uri | https://rima.ufrrj.br/jspui/handle/20.500.14407/23433 | - |
| dc.description.abstract | A Doença de Alzheimer (DA) caracteriza-se por ser um distúrbio neurodegenerativo progressivo e irreversível de memória e outras funções cognitivas, afetando o funcionamento ocupacional e social. O uso de compostos envolvendo ligantes multialvo (MTDLs), como inibidores mistos da enzima acetilcolinesterase (AChE) que atuam inibindo indiretamente a agregação do β-amiloide (Aβ) ou que combinem a inibição das colinesterases (ChEs) com outros mecanismos de ação vem sendo apontado como de grande valia para o tratamento da DA devido à possibolidade de se modular simultaneamente alvos que contribuem para a instalação e manutenção da doença. Recentemente, nosso grupo de trabalho (LaDMol-QM) descreveu duas classes de cumarinas (24 e 25a-b) que possuíam atividade inibitória mista, atuando no sítio catalítico (CAS) e periférico (PAS) ao mesmo tempo, com valores de CI50 de até 20 nM sobre a AChE e seletividades de até 354 vezes sobre a butirilcolinesterase (BChE). Tendo como base o mapa farmacofórico dessas séries, este trabalho tem como objetivo geral o planejamento, síntese e a avaliação farmacológica de uma série de benzil-triazol-cumarinas e de heterocíclos miméticos de cumarinas como possíveis agentes inibidores da enzima AChE de forma mista. Foram propostas três séries, sendo a primeira uma otimização da série triazol- cumarina, com a síntese de novos derivados benzílicos (série A), e as séries com os heterociclos miméticos quinolinona (série B) e aminoquinazolina (série C). A síntese da série A, homóloga superior da série 25, foi concluída após dez etapas sintéticas, levando a obtenção de dez novos derivados da série triazol-cumarina (26a-j), em que todos os compostos foram capazes de inibir a AChE com valores de CI50 variando de 4,2 a 103,8 nM e seletividades de até 685 vezes frente a BChE. O estudo de ancoramento molecular mostrou consistência com os resultados do estudo de cinética enzimática de compostos triazol-cumarínicos, que os classifica como inibição do tipo mista. O potencial multialvo da série A foi evidenciado pelos resultados obtidos frente a hH3R, MAO-A e MAO-B. A síntese da série B, bioisóstero clássico da série 24, foi concluída após seis etapas sintéticas, levando a obtenção de sete novos derivados da quinolinona (58a-g), que demonstraram um perfil de inibição dual das colinesterases (ChEs). Os estudos de ancoramento molecular permitiram elucidar os distintos mecanismos de inibição observados para os derivados da série B. A síntese da série C, bioisóstero não-clássico da série 24, foi realizada de forma convergente após a obtenção dos dois principais blocos de construção reacional, do fenol-2-aminoquinazolina e do cloridrato de cloroalquil piperidina, levando a obtenção de dois novos derivados da série aminoquinazolina (67a-b), que demonstraram ser capazes de inibir a BChE de forma seletiva. O estudo de ancoramento molecular mostrou consistência com os resultados do estudo de cinética enzimática, que os classifica como inibição do tipo mista. | pt_BR |
| dc.description.sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES | pt_BR |
| dc.language | por | pt_BR |
| dc.publisher | Universidade Federal Rural do Rio de Janeiro | pt_BR |
| dc.subject | Alzheimer | pt_BR |
| dc.subject | Inibidores colinesterásicos | pt_BR |
| dc.subject | Multialvo | pt_BR |
| dc.subject | cholinesterase inhibitors | pt_BR |
| dc.subject | multitarget | pt_BR |
| dc.title | Otimização Estrutural de 7-((piperidin-1-il)alcoxi)-cumarinas: Homologação e Construção de Heterociclos Miméticos Visando o Desenvolvimento de Novos Inibidores Mistos de Colinesterases | pt_BR |
| dc.title.alternative | Structural Optimization of 7-((piperidin-1-yl)alkoxy)- coumarins: Homologation and Construction of Mimetic Heterocycles Aiming at the Development of New Mixed Cholinesterase Inhibitors | en |
| dc.type | Tese | pt_BR |
| dc.description.abstractOther | Alzheimer's disease (AD) is characterized by being a progressive and irreversible neurodegenerative disorder of memory and other cognitive functions, affecting occupational and social functioning. The use of compounds involving multitarget-directed ligands (MTDLs), such as mixed inhibitors of the enzyme acetylcholinesterase (AChE) that indirectly suppress aggregation of β-amyloid (Aβ) or combine cholinesterase (ChEs) inhibition with other mechanisms, has been observed as a high-value objective for AD treatment due to the possibility to inhibit simultaneously different targets that contribute to the onset and maintenance of the disease. Recently, our research group (LaDMol-QM) described two classes of coumarins (24 and 25a-b) that exhibited mixed inhibitory activity, acting on at the catalytic site (CAS) and at the peripheral site (PAS) simultaneously, with IC50 values of up to 20 nM on AChE and selectivities of up to 354-fold over butyrylcholinesterase (BChE). Based on the pharmacophoric map of these series, this work has as its general objective the design, synthesis, and pharmacological evaluation of a series of benzyl-triazole-coumarins and coumarin mimetic heterocycles as possible mixed inhibitors of the AChE enzyme. Three series were proposed: the first, an optimization of the triazole-coumarin series involving the synthesis of new benzyl derivatives (series A); the second, a series with mimetic heterocycles, including quinolinone (series B) and aminoquinazoline (series C). The synthesis of series A, a superior homolog of series 25, was completed after ten synthetic steps, leading to the production of ten new derivatives of the triazole-coumarin series (26a-j), in which all compounds were able to inhibit AChE with IC50 values ranging from 4.2 to 103.8 nM and selectivities of up to 685-fold against BChE. The molecular docking study showed consistency with the results of the enzymatic kinetics study of triazole-coumarin compounds, which classified them as mixed-type inhibition. The multitarget potential of series A was demonstrated by the results obtained against hH3R, MAO-A, and MAO-B. The synthesis of series B, a classical bioisostere of series 24, was completed after six synthetic steps, leading to the production of seven new quinolinone derivatives (58a-g), which demonstrated a dual inhibition profile of cholinesterases (ChEs). Molecular docking studies elucidated the distinct inhibition mechanisms observed for the B series derivatives. The synthesis of the C series, a non-classical bioisostere of the 24 series, was performed in a convergent manner after obtaining the two main reaction building blocks, phenol-2-amino quinazoline and chloroalkyl piperidine hydrochloride, leading to the production of two new derivatives of the amino quinazoline series (67a-b), which were shown to be capable of inhibiting BChE selectively. The molecular docking study showed consistency with the results of the enzyme kinetics study, which classified them as mixed-type inhibition. | en |
| dc.contributor.advisor1 | Kümmerle, Arthur Eugen | - |
| dc.contributor.advisor1Lattes | http://lattes.cnpq.br/5598000938584486 | pt_BR |
| dc.contributor.referee1 | Kümmerle, Arthur Eugen | - |
| dc.contributor.referee1Lattes | http://lattes.cnpq.br/5598000938584486 | pt_BR |
| dc.contributor.referee2 | Lima, Aurea Echevarria Aznar Neves | - |
| dc.contributor.referee2Lattes | http://lattes.cnpq.br/1879077396134052 | pt_BR |
| dc.contributor.referee3 | Caleffi, Guilherme da Silva | - |
| dc.contributor.referee3ID | https://orcid.org/0000-0001-9703-3404 | pt_BR |
| dc.contributor.referee3Lattes | http://lattes.cnpq.br/5663421512698987 | pt_BR |
| dc.contributor.referee4 | Sant'Anna, Carlos Mauricio Rabello de | - |
| dc.contributor.referee4ID | https://orcid.org/0000-0003-1989-5038 | pt_BR |
| dc.contributor.referee4Lattes | http://lattes.cnpq.br/2087099684752643 | pt_BR |
| dc.contributor.referee5 | Pinheiro, Pedro de Sena Murteira | - |
| dc.contributor.referee5ID | https://orcid.org/0000-0003-4148-4243 | pt_BR |
| dc.contributor.referee5Lattes | http://lattes.cnpq.br/5967618384293645 | pt_BR |
| dc.creator.ID | https://orcid.org/0000-0002-5948-5810 | pt_BR |
| dc.creator.Lattes | http://lattes.cnpq.br/4851384421417833 | pt_BR |
| dc.publisher.country | Brasil | pt_BR |
| dc.publisher.department | Instituto de Química | pt_BR |
| dc.publisher.initials | UFRRJ | pt_BR |
| dc.publisher.program | Programa de Pós-Graduação em Química | pt_BR |
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