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http://rima110.im.ufrrj.br:8080/jspui/handle/20.500.14407/23509Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Souza, Bruna Caroline Esteves de | - |
| dc.date.accessioned | 2025-10-28T13:21:19Z | - |
| dc.date.available | 2025-10-28T13:21:19Z | - |
| dc.date.issued | 2024-09-16 | - |
| dc.identifier.citation | SOUZa, Bruna Caroline Esteves de. Planejamento, Síntese e Avaliação Farmacológica de Bases de Mannich Derivadas da Lausona: Potenciais Agentes Antimaláricos e Anticolinesterásicos. 2024. 297 f. Dissertação (Mestrado em Química) -Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2024. | pt_BR |
| dc.identifier.uri | https://rima.ufrrj.br/jspui/handle/20.500.14407/23509 | - |
| dc.description.abstract | Esta dissertação aborda duas doenças: malária e doença de Alzheimer. A malária, causada por protozoários Plasmodium, é um grave problema de saúde devido à crescente resistência dos parasitas aos antimaláricos, como atovaquona, que inibe o complexo III da cadeia respiratória. A doença de Alzheimer é uma neurodegeneração que compromete a cognição mental e é tratada com fármacos que aumentam os níveis de neurotransmissores, como donepezila, um inibidor de colinesterase que eleva os níveis de acetilcolina. A lausona, uma naftoquinona extraída das plantas Lawsonia inermis (hena) e Eichhornia crassipes (jacinto-de- água), usada na reação multicomponente de Mannich para sintetizar bases de Mannich com potencial antimalárico e inibidor de colinesterase, abrindo novas perspectivas para o desenvolvimento de fármacos por uma abordagem sintética simples e econômica. A atovaquona e a donepezila foram referências para planejar 16 bases de Mannich derivadas da lausona, com base em estudos in silico de docking. Três estratégias de planejamento foram utilizadas: bioisosterismo, homologação e simplificação molecular. As bases de Mannich foram divididas em duas séries: monoaminas alifáticas não cíclicas (BS1 - BS11) e diaminas bicíclicas (BS12 - BS16). A série de diaminas bicíclicas (BS12 - BS16) apresenta semelhança com aminonaftoquinonas bioissteras da donepezila, mantendo a subunidade benzilpiperidina e substituindo o esqueleto central por naftoquinona. Monoaminas alifáticas não cíclicas (BS3, BS9 e BS10) também se assemelham a base de Mannich avaliadas para inibição de colinesterase. As bases de Mannich (BS1 - BS16) foram sintetizadas pela reação multicomponente de Mannich com a lausona, três aldeídos (formaldeído, acetaldeído e benzaldeído) e aminas distintas, seguida de purificação por recristalização, com rendimentos de 30 a 90%. Para melhorar a solubilidade, foram convertidas em cloridratos, com pureza confirmada por Cromatografia Líquida de Alta Eficiência (CLAE), resultando em monocloridratos BS1.HCl – BS12.HCl (LaDMol365 – LaDMol377) e dicloridrato BS13.2HCl (LaDMol377). As estruturas foram confirmadas por Espectrometria de Massas e RMN (1H e 13C). Estudos in sílico das propriedades farmacocinéticas foram realizados. A atividade antimalárica de BS1.HCl – BS12.HCl (LaDMol365 – LaDMol377) está em andamento, com os resultados a serem publicados. Ensaios de inibição de colinesterase (AChE e BChE) em concentração única de 30 μM mostraram que BS13.2HCl (LaDMol377) e BS9.HCl (LaDMol374) apresentaram perfil promissor para inibição de AChE, incentivando a continuidade dos estudos enzimáticos. | pt_BR |
| dc.description.sponsorship | Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq | pt_BR |
| dc.description.sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES | pt_BR |
| dc.description.sponsorship | Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro - FAPERJ | pt_BR |
| dc.language | por | pt_BR |
| dc.publisher | Universidade Federal Rural do Rio de Janeiro | pt_BR |
| dc.subject | Lawsonia inermis | pt_BR |
| dc.subject | reação de Mannich | pt_BR |
| dc.subject | avaliação farmacológica | pt_BR |
| dc.subject | Lawsonia inermis | pt_BR |
| dc.subject | Mannich reaction | pt_BR |
| dc.subject | pharmacological evaluation | pt_BR |
| dc.title | Planejamento, síntese e avaliação farmacológica de bases de mannich derivadas da lausona: potenciais agentes antimaláricos e anticolinesterásicos. | pt_BR |
| dc.title.alternative | Design, synthesis and pharmacological evaluation of mannich bases derived from lausone: potential antimalarial and anticholinesterase agents. | en |
| dc.type | Dissertação | pt_BR |
| dc.description.abstractOther | This dissertation addresses two diseases: malaria and Alzheimer's disease. Malaria, caused by Plasmodium protozoa, is a serious health problem due to the increasing resistance of the parasites to antimalarials, such as atovaquone, which inhibits complex III of the respiratory chain. Alzheimer's disease is a neurodegeneration that compromises mental cognition and is treated with drugs that increase neurotransmitter levels, such as donepezil, a cholinesterase inhibitor that increases acetylcholine levels. Lausone, a naphthoquinone extracted from the plants Lawsonia inermis (henna) and Eichhornia crassipes (water hyacinth), is used in the multicomponent Mannich reaction to synthesize Mannich bases with antimalarial and cholinesterase inhibitor potential, opening new perspectives for the development of drugs through a simple and economical synthetic approach. Atovaquone and donepezil were references for the design of 16 Mannich bases derived from lausanne, based on in silico docking studies. Three design strategies were used: bioisosterism, homologation and molecular simplification. The Mannich bases were divided into two series: non-cyclic aliphatic monoamines (BS1 - BS11) and bicyclic diamines (BS12 - BS16). The series of bicyclic diamines (BS12 - BS16) shows similarity to the aminonaphthoquinone bioisosteres of donepezil, maintaining the benzylpiperidine subunit and replacing the central skeleton with naphthoquinone. Non-cyclic aliphatic monoamines (BS3, BS9 and BS10) also resemble the Mannich bases evaluated for cholinesterase inhibition. Mannich bases (BS1 - BS16) were synthesized by the multicomponent Mannich reaction with lausone, three aldehydes (formaldehyde, acetaldehyde and benzaldehyde) and different amines, followed by purification by recrystallization, with yields of 30 to 90%. To improve solubility, they were converted into hydrochlorides, with purity confirmed by High Performance Liquid Chromatography (HPLC), resulting in monohydrochlorides BS1.HCl - BS12.HCl (LaDMol365 - LaDMol377) and dihydrochloride BS13.2HCl (LaDMol377). The structures were confirmed by Mass Spectrometry and NMR (1H and 13C). In silico studies of pharmacokinetic properties were performed. The antimalarial activity of BS1.HCl – BS12.HCl (LaDMol365 – LaDMol377) is ongoing, with results to be published. Cholinesterase inhibition assays (AChE and BChE) at a single concentration of 30 μM showed that BS13.2HCl (LaDMol377) and BS9.HCl (LaDMol374) presented a promising profile for AChE inhibition, encouraging the continuation of enzymatic studies. | en |
| dc.contributor.advisor1 | Kümmerle, Arthur Eugen | - |
| dc.contributor.advisor1Lattes | http://lattes.cnpq.br/5598000938584486 | pt_BR |
| dc.contributor.advisor-co1 | Graebin, Cedric Stephan | - |
| dc.contributor.advisor-co1ID | https://orcid.org/0000-0003-1410-1227 | pt_BR |
| dc.contributor.advisor-co1Lattes | http://lattes.cnpq.br/4900857097448760 | pt_BR |
| dc.contributor.referee1 | Kümmerle, Arthur Eugen | - |
| dc.contributor.referee1Lattes | http://lattes.cnpq.br/5598000938584486 | pt_BR |
| dc.contributor.referee2 | Suzart, Luciano Ramos | - |
| dc.contributor.referee2Lattes | http://lattes.cnpq.br/9433715032329261 | pt_BR |
| dc.contributor.referee3 | Vieira, Daniel Pais Pires | - |
| dc.contributor.referee3Lattes | http://lattes.cnpq.br/8564684974338964 | pt_BR |
| dc.creator.Lattes | - | 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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Biomedicine & Pharmacotherapy, v. 146, p. 112556, 2022. | pt_BR |
| dc.subject.cnpq | Química | pt_BR |
| Appears in Collections: | Mestrado em Química | |
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