Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos
Ano de defesa: | 2023 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | , , , |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de Santa Maria
Centro de Ciências Naturais e Exatas |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Química
|
Departamento: |
Química
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/28378 |
Resumo: | This thesis presents the results related to the synthesis, structural characterization and evaluation of the in vitro enzymatic inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) of novel series of heterocycle hybrids analogous to 9-amino-1,2,3,4-tetrahydroacridine (Tacrine -THA), which contains thiophenes, 1,2,3-triazoles, isoxazoles, pyrroles and spiro-chromenes as structural modifiers and aimed at generating possible prodrugs in the treatment of Alzheimer's disease (AD). This work also presents a study of N-derivatization aiming the insertion of pyrroles, via Clauson-Kaas reaction, in order to investigate photophysical properties of interest (absorption and emission). Thus, three hybrid series were initially obtained, conjugating different five-membered heterocycles (thienopyridinamines, isoxazolopyridinamines and [1,2,3]triazolopyridinamines) to THA. For this purpose, heteroaryl-2-aminocarbonitriles (thiophene-, isoxazole- and 1,2,3-triazole-derivatives), simple cycloalkanones (cyclopentanone, cyclohexanone, cycloheptanone and 1-tetralone) and more complex ones (spiro[chroman-2,1 '-cycloalkan]-4-ones) were applied as building blocks. Thus, 34 (thirty-four) heterocycles analogous to THA were isolated and characterized in yields ranging to 4% - 88%, depending on the precursor carbonitriles, through methodologies that used AlCl3 as catalyst, in the absence or presence of solvent, under conventional thermal heating or by microwave irradiation. In sequence, the three new series of tacrine analogues (thiophene-, isoxazole- and 1,2,3-triazole-hybrids) were evaluated for their in vitro AChE and BChE inhibition activity. The experimental results of enzymatic inhibition were added to complementary studies of molecular docking and showed that all the developed compounds demonstrated better anti-ChE properties promising for the inhibition of BChE, possibly due to the size that the AChE active site has, being smaller than the of BChE, which could explain because the compounds are better inhibitors of BChE than AChE. In addition, N-derivatization reactions, enabling the construction of derivative pyrroles, via the Clauson-Kaas reaction, were applied to the modified thiophene-tacrines, leading to the obtainment of 12 (twelve) novel pyrroles in yields of 66% - 95%. These pyrrole derivatives had their photophysical properties investigated (absorption and emission) in solution (CHCl3). As a result, it was found that these pyrroles were the transition bands were observed in the ultraviolet region, with two main maximum absorption bands (280 and 350 nm), and exhibit fluorescence in solution (380-400 nm) and lifetime decay values of fluorescence (1.49-2.60 ns) are directly related and dependent on the substituents directly linked to the thiophene moiety of the compounds. All chemical compounds related to the novel series produced in this thesis were characterized by melting point and structurally elucidated via routine spectroscopic and spectrometric techniques, such as uni- (1H and 13C) and two-dimensional (HSQC and HMBC) NMR in solution, HRMS and single crystal X-ray diffraction. |
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2023-03-24T15:46:05Z2023-03-24T15:46:05Z2023-01-27http://repositorio.ufsm.br/handle/1/28378This thesis presents the results related to the synthesis, structural characterization and evaluation of the in vitro enzymatic inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) of novel series of heterocycle hybrids analogous to 9-amino-1,2,3,4-tetrahydroacridine (Tacrine -THA), which contains thiophenes, 1,2,3-triazoles, isoxazoles, pyrroles and spiro-chromenes as structural modifiers and aimed at generating possible prodrugs in the treatment of Alzheimer's disease (AD). This work also presents a study of N-derivatization aiming the insertion of pyrroles, via Clauson-Kaas reaction, in order to investigate photophysical properties of interest (absorption and emission). Thus, three hybrid series were initially obtained, conjugating different five-membered heterocycles (thienopyridinamines, isoxazolopyridinamines and [1,2,3]triazolopyridinamines) to THA. For this purpose, heteroaryl-2-aminocarbonitriles (thiophene-, isoxazole- and 1,2,3-triazole-derivatives), simple cycloalkanones (cyclopentanone, cyclohexanone, cycloheptanone and 1-tetralone) and more complex ones (spiro[chroman-2,1 '-cycloalkan]-4-ones) were applied as building blocks. Thus, 34 (thirty-four) heterocycles analogous to THA were isolated and characterized in yields ranging to 4% - 88%, depending on the precursor carbonitriles, through methodologies that used AlCl3 as catalyst, in the absence or presence of solvent, under conventional thermal heating or by microwave irradiation. In sequence, the three new series of tacrine analogues (thiophene-, isoxazole- and 1,2,3-triazole-hybrids) were evaluated for their in vitro AChE and BChE inhibition activity. The experimental results of enzymatic inhibition were added to complementary studies of molecular docking and showed that all the developed compounds demonstrated better anti-ChE properties promising for the inhibition of BChE, possibly due to the size that the AChE active site has, being smaller than the of BChE, which could explain because the compounds are better inhibitors of BChE than AChE. In addition, N-derivatization reactions, enabling the construction of derivative pyrroles, via the Clauson-Kaas reaction, were applied to the modified thiophene-tacrines, leading to the obtainment of 12 (twelve) novel pyrroles in yields of 66% - 95%. These pyrrole derivatives had their photophysical properties investigated (absorption and emission) in solution (CHCl3). As a result, it was found that these pyrroles were the transition bands were observed in the ultraviolet region, with two main maximum absorption bands (280 and 350 nm), and exhibit fluorescence in solution (380-400 nm) and lifetime decay values of fluorescence (1.49-2.60 ns) are directly related and dependent on the substituents directly linked to the thiophene moiety of the compounds. All chemical compounds related to the novel series produced in this thesis were characterized by melting point and structurally elucidated via routine spectroscopic and spectrometric techniques, such as uni- (1H and 13C) and two-dimensional (HSQC and HMBC) NMR in solution, HRMS and single crystal X-ray diffraction.A presente tese descreve os resultados relacionados à síntese, caracterização estrutural e avaliação da inibição enzimática in vitro de acetilcolinesterase (AChE) e butirilcolinesterase (BChE) de séries inéditas de heterociclos híbridos análogos à 9-amino-1,2,3,4-tetrahidroacridina (Tacrina -THA), as quais contém tiofenos, 1,2,3-triazóis, isoxazóis, pirróis e espiro-cromenos como modificadores estruturais e direcionados a geração de possíveis pró-fármacos no tratamento da doença de Alzheimer (DA). Este trabalho apresenta também um estudo de N-derivatização visando a inserção de pirróis, via reação de Clauson-Kaas, objetivando investigar propriedades fotofísicas de interesse (absorção e emissão). Assim, inicialmente foram obtidas três séries híbridas, conjugando diferentes heterociclos de cinco membros (tienopiridinaminas, isoxazolopiridinaminas e [1,2,3]triazolopiridinaminas) à THA. Para tanto, heteroaril-2-aminocarbonitrilas (tiofeno-, isoxazol- e 1,2,3-triazol-derivadas), cicloalcanonas simples (ciclopentanona, ciclohexanona, cicloheptanona e 1-tetralona) e mais complexas (espiro[cromano-2,1'-cicloalcan]-4-onas) foram utilizadas como blocos precursores. Deste modo, foram isolados e caracterizados 34 (trinta e quatro) heterociclos análogos à THA em rendimentos na faixa de 4% - 88 %, dependendo das carbonitrilas precursoras, por meio de metodologias que utilizaram AlCl3 como ácido de Lewis, na ausência ou presença de solvente, sob aquecimento térmico convencional ou por irradiação de micro-ondas. Em sequência, as três novas séries de tacrinas análogas (tiofeno-, isoxazol- e 1,2,3-triazol-híbridas), foram avaliadas quanto a sua atividade de inibição da AChE e BChE in vitro. Os resultados experimentais de inibição enzimática foram agregados a estudos complementares de docking molecular e evidenciaram que todos os compostos desenvolvidos demonstraram melhores propriedades anti-ChEs promissoras para a inibição da BChE, possivelmente devido ao tamanho que o sítio ativo da AChE possui, sendo menor que o da BChE, o que poderia explicar a causa dos compostos serem melhores inibidores de BChE do que AChE. Além disso, reações de N-derivatização, possibilitando a construção de pirróis derivados, via reação de Clauson-Kaas, foram aplicadas às tiofeno-tacrinas modificadas, levando à obtenção de 12 (doze) pirróis inéditos em rendimentos de 66% - 95%. Estes derivados pirrólicos tiveram suas propriedades fotofísicas investigadas (absorção e emissão), em solução (CHCl3). Como resultado, verificou-se que estes pirróis absorvem na região do ultravioleta, com duas principais bandas de absorção máxima (280 e 350 nm), e apresentam fluorescência em solução (380-400 nm) e os valores de tempo de vida de fluorescência (1,49-2,60 ns) estão diretamente relacionados e dependentes dos substituintes ligados diretamente à porção tiofênica dos compostos. Todos os compostos químicos relativos às séries inéditas produzidas nesta tese foram caracterizados por ponto de fusão e elucidados estruturalmente via técnicas espectroscópicas e espectrométricas de rotina, como RMN uni- (1H e 13C) e bidimensionais (HSQC e HMBC) em solução, HRMS e difração de raios-X em monocristal.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências Naturais e ExatasPrograma de Pós-Graduação em QuímicaUFSMBrasilQuímicaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessTacrina análogosTiofenosIsoxazóis1,2,3-TriazóisInibição enzimáticaPropriedades fotofísicasTacrine analoguesThiophenesIsoxazoles1,2,3-TriazolesEnzyme inhibitionPhotophysical propertiesCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICATacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridosTacrine analogues: synthesis, derivatization, bioactivity and photophysics of heterocyclic hybrid systemsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisBonacorso, Helio Gauzehttp://lattes.cnpq.br/7275608974248322Martins, Marcos Antonio PintoMerlo, Aloir AntonioFrizzo, Clarissa PiccininGodoi, Marcelo deSchumacher, Ricardo Fredericohttp://lattes.cnpq.br/0190842021073920Kappenberg, Yúri Giovane10060000000060060060060060060060060006c852ad-d805-43c3-99d6-93a6a86f507c6973021c-5f56-4019-b42b-c4b3a82af06650c581cd-b8f5-4988-a3f5-6c12e2e88fa6fa2e7141-9b4f-43d6-a7af-6718960f91a7d15b5067-d5ab-4a9f-9e0c-a1122d544ef0773f0cd6-74a3-4fd2-86eb-2b5a2b2f3b166c8d4d2c-6e7a-4fa7-8f85-f8e27a24863breponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALTES_PPGQUIMICA_2023_KAPPENBERG_YURI.pdfTES_PPGQUIMICA_2023_KAPPENBERG_YURI.pdfTeseapplication/pdf20055299http://repositorio.ufsm.br/bitstream/1/28378/1/TES_PPGQUIMICA_2023_KAPPENBERG_YURI.pdfa839577e68c8003ecdcaa4b22ed33c20MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
dc.title.alternative.eng.fl_str_mv |
Tacrine analogues: synthesis, derivatization, bioactivity and photophysics of heterocyclic hybrid systems |
title |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
spellingShingle |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos Kappenberg, Yúri Giovane Tacrina análogos Tiofenos Isoxazóis 1,2,3-Triazóis Inibição enzimática Propriedades fotofísicas Tacrine analogues Thiophenes Isoxazoles 1,2,3-Triazoles Enzyme inhibition Photophysical properties CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
title_full |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
title_fullStr |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
title_full_unstemmed |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
title_sort |
Tacrina análogos: síntese, derivatização, bioatividade e fotofísica de sistemas heterocíclicos híbridos |
author |
Kappenberg, Yúri Giovane |
author_facet |
Kappenberg, Yúri Giovane |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Bonacorso, Helio Gauze |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/7275608974248322 |
dc.contributor.advisor-co1.fl_str_mv |
Martins, Marcos Antonio Pinto |
dc.contributor.referee1.fl_str_mv |
Merlo, Aloir Antonio |
dc.contributor.referee2.fl_str_mv |
Frizzo, Clarissa Piccinin |
dc.contributor.referee3.fl_str_mv |
Godoi, Marcelo de |
dc.contributor.referee4.fl_str_mv |
Schumacher, Ricardo Frederico |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/0190842021073920 |
dc.contributor.author.fl_str_mv |
Kappenberg, Yúri Giovane |
contributor_str_mv |
Bonacorso, Helio Gauze Martins, Marcos Antonio Pinto Merlo, Aloir Antonio Frizzo, Clarissa Piccinin Godoi, Marcelo de Schumacher, Ricardo Frederico |
dc.subject.por.fl_str_mv |
Tacrina análogos Tiofenos Isoxazóis 1,2,3-Triazóis Inibição enzimática Propriedades fotofísicas |
topic |
Tacrina análogos Tiofenos Isoxazóis 1,2,3-Triazóis Inibição enzimática Propriedades fotofísicas Tacrine analogues Thiophenes Isoxazoles 1,2,3-Triazoles Enzyme inhibition Photophysical properties CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.eng.fl_str_mv |
Tacrine analogues Thiophenes Isoxazoles 1,2,3-Triazoles Enzyme inhibition Photophysical properties |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
This thesis presents the results related to the synthesis, structural characterization and evaluation of the in vitro enzymatic inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) of novel series of heterocycle hybrids analogous to 9-amino-1,2,3,4-tetrahydroacridine (Tacrine -THA), which contains thiophenes, 1,2,3-triazoles, isoxazoles, pyrroles and spiro-chromenes as structural modifiers and aimed at generating possible prodrugs in the treatment of Alzheimer's disease (AD). This work also presents a study of N-derivatization aiming the insertion of pyrroles, via Clauson-Kaas reaction, in order to investigate photophysical properties of interest (absorption and emission). Thus, three hybrid series were initially obtained, conjugating different five-membered heterocycles (thienopyridinamines, isoxazolopyridinamines and [1,2,3]triazolopyridinamines) to THA. For this purpose, heteroaryl-2-aminocarbonitriles (thiophene-, isoxazole- and 1,2,3-triazole-derivatives), simple cycloalkanones (cyclopentanone, cyclohexanone, cycloheptanone and 1-tetralone) and more complex ones (spiro[chroman-2,1 '-cycloalkan]-4-ones) were applied as building blocks. Thus, 34 (thirty-four) heterocycles analogous to THA were isolated and characterized in yields ranging to 4% - 88%, depending on the precursor carbonitriles, through methodologies that used AlCl3 as catalyst, in the absence or presence of solvent, under conventional thermal heating or by microwave irradiation. In sequence, the three new series of tacrine analogues (thiophene-, isoxazole- and 1,2,3-triazole-hybrids) were evaluated for their in vitro AChE and BChE inhibition activity. The experimental results of enzymatic inhibition were added to complementary studies of molecular docking and showed that all the developed compounds demonstrated better anti-ChE properties promising for the inhibition of BChE, possibly due to the size that the AChE active site has, being smaller than the of BChE, which could explain because the compounds are better inhibitors of BChE than AChE. In addition, N-derivatization reactions, enabling the construction of derivative pyrroles, via the Clauson-Kaas reaction, were applied to the modified thiophene-tacrines, leading to the obtainment of 12 (twelve) novel pyrroles in yields of 66% - 95%. These pyrrole derivatives had their photophysical properties investigated (absorption and emission) in solution (CHCl3). As a result, it was found that these pyrroles were the transition bands were observed in the ultraviolet region, with two main maximum absorption bands (280 and 350 nm), and exhibit fluorescence in solution (380-400 nm) and lifetime decay values of fluorescence (1.49-2.60 ns) are directly related and dependent on the substituents directly linked to the thiophene moiety of the compounds. All chemical compounds related to the novel series produced in this thesis were characterized by melting point and structurally elucidated via routine spectroscopic and spectrometric techniques, such as uni- (1H and 13C) and two-dimensional (HSQC and HMBC) NMR in solution, HRMS and single crystal X-ray diffraction. |
publishDate |
2023 |
dc.date.accessioned.fl_str_mv |
2023-03-24T15:46:05Z |
dc.date.available.fl_str_mv |
2023-03-24T15:46:05Z |
dc.date.issued.fl_str_mv |
2023-01-27 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/28378 |
url |
http://repositorio.ufsm.br/handle/1/28378 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
100600000000 |
dc.relation.confidence.fl_str_mv |
600 600 600 600 600 600 600 600 |
dc.relation.authority.fl_str_mv |
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dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Química |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Química |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências Naturais e Exatas |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações do UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
instname_str |
Universidade Federal de Santa Maria (UFSM) |
instacron_str |
UFSM |
institution |
UFSM |
reponame_str |
Biblioteca Digital de Teses e Dissertações do UFSM |
collection |
Biblioteca Digital de Teses e Dissertações do UFSM |
bitstream.url.fl_str_mv |
http://repositorio.ufsm.br/bitstream/1/28378/1/TES_PPGQUIMICA_2023_KAPPENBERG_YURI.pdf http://repositorio.ufsm.br/bitstream/1/28378/2/license_rdf http://repositorio.ufsm.br/bitstream/1/28378/3/license.txt |
bitstream.checksum.fl_str_mv |
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bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM) |
repository.mail.fl_str_mv |
atendimento.sib@ufsm.br||tedebc@gmail.com |
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