Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico
Ano de defesa: | 2015 |
---|---|
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
|
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Química
|
Departamento: |
Química
|
País: |
BR
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://repositorio.ufsm.br/handle/1/4276 |
Resumo: | This work reports the synthesis of a series of 29 new 1-(3-aryl-4,5-dihydroisoxazol-5-yl)methyl-4-trihalomethylpyrimidin-2(1H)-ones which have high pharmacological interest, since they are similar to natural and synthetic nucleosides. These compounds were obtained from 1,3-dippolar cycloaddition reaction between the 1-allyl-(6-aryl)-4-trihalomethylpyrimidin-2(1H)-ones and different benzonitrile oxides, obtained from the selected oximes of general formula ArCH=NOH (where Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, styryl, 2-OHC6H4 e 4-OHC6H4). The reaction conditions employed were highly regioselective, because it was observed the formation of only 3,5-substituted isomer by both NMR spectral analysis and X-ray diffractometry. The compounds were obtained in good yields (58 99%) and were purified from recrystallization or by column chromatography on silica gel. Some the obtained compounds showed antineoplastic activity in vitro against different tumor cell lines. Additionally, three new N3-substituted pyrimidinic dideoxynucleoside analogues were prepared, which were obtained in good yields (88 97%) from the reaction of N-allyl-2-methylthiopyrimidin-4(3H)-one and some of the benzonitrile oxides mentioned above. The reactions for the formation of N3-substituted nucleoside still require optimization. This thesis also described the regiochemisty controled synthesis of two series of pyrazoles, named 5(3)-aryl-3(5)-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides, structural analogues of Celecoxib (14 examples), where aryl = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, furan-2-yl, from the cyclocondensation reaction between 4-aryl-1,1,1-trifluoromethyl-4-methoxy-3-buten-2-ones and 4-hydrazinobenzenosulfonamide hydrochloride. The isolation of either isomer depended on the initial pH medium, where the alkaline pH favored the isolation of the 1,5-substituted isomer at yields of 73 99% and the reaction conducted in acid pH favored the isolation of the 1,3-substituted isomer, with yields of 77 94%. This study also allowed the isolation and spectroscopic characterization of a novel series of 3-aryl(heteroaryl)-5-hydroxy-5-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides (7 examples) in yields of 75 97% with interesting anti-inflammatory and antinociceptive activities in vivo. |
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2016-04-282016-04-282015-05-29LOBO, Marcio Marçal. Regioselective synthesis of Dideoxynucleosides and 3(5)-Trifluoromethyl-1H-pyrazoles of pharmacological interest. 2015. 298 f. Tese (Doutorado em Química) - Universidade Federal de Santa Maria, Santa Maria, 2015.http://repositorio.ufsm.br/handle/1/4276This work reports the synthesis of a series of 29 new 1-(3-aryl-4,5-dihydroisoxazol-5-yl)methyl-4-trihalomethylpyrimidin-2(1H)-ones which have high pharmacological interest, since they are similar to natural and synthetic nucleosides. These compounds were obtained from 1,3-dippolar cycloaddition reaction between the 1-allyl-(6-aryl)-4-trihalomethylpyrimidin-2(1H)-ones and different benzonitrile oxides, obtained from the selected oximes of general formula ArCH=NOH (where Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, styryl, 2-OHC6H4 e 4-OHC6H4). The reaction conditions employed were highly regioselective, because it was observed the formation of only 3,5-substituted isomer by both NMR spectral analysis and X-ray diffractometry. The compounds were obtained in good yields (58 99%) and were purified from recrystallization or by column chromatography on silica gel. Some the obtained compounds showed antineoplastic activity in vitro against different tumor cell lines. Additionally, three new N3-substituted pyrimidinic dideoxynucleoside analogues were prepared, which were obtained in good yields (88 97%) from the reaction of N-allyl-2-methylthiopyrimidin-4(3H)-one and some of the benzonitrile oxides mentioned above. The reactions for the formation of N3-substituted nucleoside still require optimization. This thesis also described the regiochemisty controled synthesis of two series of pyrazoles, named 5(3)-aryl-3(5)-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides, structural analogues of Celecoxib (14 examples), where aryl = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, furan-2-yl, from the cyclocondensation reaction between 4-aryl-1,1,1-trifluoromethyl-4-methoxy-3-buten-2-ones and 4-hydrazinobenzenosulfonamide hydrochloride. The isolation of either isomer depended on the initial pH medium, where the alkaline pH favored the isolation of the 1,5-substituted isomer at yields of 73 99% and the reaction conducted in acid pH favored the isolation of the 1,3-substituted isomer, with yields of 77 94%. This study also allowed the isolation and spectroscopic characterization of a novel series of 3-aryl(heteroaryl)-5-hydroxy-5-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides (7 examples) in yields of 75 97% with interesting anti-inflammatory and antinociceptive activities in vivo.Esta tese apresenta a síntese de uma série de 29 moléculas inéditas de 1-(3-aril-4,5-diidroisoxazol-5-il)metil-4-trialometilpirimidin-2(1H)-onas que possuem alto interesse farmacológico, visto que são análogos a nucleosídeos naturais e sintéticos. Esses compostos foram obtidos a partir de reação de cicloadição 1,3-dipolar entre as 1-alil-(6-aril)-4-trialometilpirimidin-2(1H)-onas e diferentes óxidos de benzonitrila, obtidos a partir das oximas selecionadas, de fórmula geral ArCH=NOH (onde Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, Estiril, 2-OHC6H4 e 4-OHC6H4). As condições reacionais empregadas mostraram-se altamente regiosseletivas, uma vez que, por análise dos espectros de RMN e por difratometria de raios-X, observou-se a formação apenas do isômero 3,5-substituído. Os compostos foram obtidos em bons rendimentos (58 99%) e puderam ser purificados a partir de recristalização ou através de coluna cromatográfica em sílica gel. Alguns dos compostos obtidos apresentaram atividade antineoplásica in vitro frente a diferentes linhagens de células tumorais. Também estão apresentados 3 novos análogos nucleosídeos pirimidínicos N3-substituídos, obtidos em bons rendimentos (88 97%) a partir da reação da N-alil-2-metiltiopirimidin-4(3H)-ona e de alguns óxidos de benzonitrila acima citados. As reações para a formação dos nucleosídeos N3-substituídos ainda necessitam de otimização. Nesta tese também está descrito o controle regioquímico para a síntese de duas séries de pirazóis, nomeados 5(3)-aril-3(5)-trifluormetil-(1H-pirazol-1-il)benzenosulfonamidas, análogos estruturais do Celecoxib (14 exemplos), onde aril = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, fur-2-il, a partir da reação de ciclocondensação entre 4-aril-1,1,1-trifluormetil-4-metóxi-3-buten-2-onas e o cloridrato de 4-hidrazinilbenzenosulfonamida. O isolamento de um ou outro isômero dependeu do pH inicial do meio, onde o pH básico favoreceu o isolamento do isômero 1,5-substituido com rendimentos de 73 99% e a reação conduzida em pH ácido favoreceu o isolamento do isômero 1,3-substituído, com rendimentos de 77 94%. Este estudo também possibilitou o isolamento e caracterização espectroscópica de uma série inédita de 3-aril(heteroaril)-5-hidróxi-5-trifluormetil-(1H-pirazol-1-il)benzenosulfonamidas (7 exemplos) em rendimentos de 75 97%, com interessante atividade anti-inflamatória e antinociceptiva in vivo.Conselho Nacional de Desenvolvimento Científico e Tecnológicoapplication/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em QuímicaUFSMBRQuímicaCicloadição 1,3-dipolarIsoxazolPirazolNucleosídeoCelecoxibRegiosseletividadeTrifluormetil-1H-pirazol1,3-dipolar cycloadditionIsoxazolePyrazoleNucleosideCelecoxibRegioselectivityTrifluoromethyl-1H-pyrazoleCNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICASíntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológicoRegioselective synthesis of Dideoxynucleosides and 3(5)-Trifluoromethyl-1H-pyrazoles of pharmacological interestinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisZanatta, Nilohttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783100P9Morel, Ademir Fariashttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783930A8Frizzo, Clarissa Piccininhttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4757171J0Fantinel, Leonardohttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4777461U9Amaral, Simone Schneiderhttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4764345U8http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4240255Z6Lobo, Marcio Marçal100600000000400300300500300300300233dc1de-ab03-4f57-9b85-e40dc01a2d4fc6bd5528-d450-4368-8e98-de23fc46b18d22df5f67-c304-4742-b982-4d1e6d30aeccd15b5067-d5ab-4a9f-9e0c-a1122d544ef0eba5e7a6-11ae-4c8d-8467-992f3d7d46e6f86fa1dd-3dbf-4dc5-84f9-ad0b1b05c5b1info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALLOBO, MARCIO MARCAL.pdfapplication/pdf22755238http://repositorio.ufsm.br/bitstream/1/4276/1/LOBO%2c%20MARCIO%20MARCAL.pdf2f9c5e8ca461e89c05e8cd8599d016e7MD51TEXTLOBO, MARCIO MARCAL.pdf.txtLOBO, MARCIO MARCAL.pdf.txtExtracted texttext/plain352567http://repositorio.ufsm.br/bitstream/1/4276/2/LOBO%2c%20MARCIO%20MARCAL.pdf.txt6882c090ed0456c2612c01f92014b118MD52THUMBNAILLOBO, MARCIO MARCAL.pdf.jpgLOBO, MARCIO MARCAL.pdf.jpgIM Thumbnailimage/jpeg5664http://repositorio.ufsm.br/bitstream/1/4276/3/LOBO%2c%20MARCIO%20MARCAL.pdf.jpgfb0827bf6ba06addb23d6223b6c2466eMD531/42762017-07-25 11:05:02.746oai:repositorio.ufsm.br:1/4276Repositório Institucionalhttp://repositorio.ufsm.br/PUBhttp://repositorio.ufsm.br/oai/requestopendoar:39132017-07-25T14:05:02Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
dc.title.alternative.eng.fl_str_mv |
Regioselective synthesis of Dideoxynucleosides and 3(5)-Trifluoromethyl-1H-pyrazoles of pharmacological interest |
title |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
spellingShingle |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico Lobo, Marcio Marçal Cicloadição 1,3-dipolar Isoxazol Pirazol Nucleosídeo Celecoxib Regiosseletividade Trifluormetil-1H-pirazol 1,3-dipolar cycloaddition Isoxazole Pyrazole Nucleoside Celecoxib Regioselectivity Trifluoromethyl-1H-pyrazole CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
title_full |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
title_fullStr |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
title_full_unstemmed |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
title_sort |
Síntese regiosseletiva de Dideoxinucleosídeos e 3(5)-Trifluormetil-1H-pirazóis de interesse farmacológico |
author |
Lobo, Marcio Marçal |
author_facet |
Lobo, Marcio Marçal |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Zanatta, Nilo |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783100P9 |
dc.contributor.referee1.fl_str_mv |
Morel, Ademir Farias |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4783930A8 |
dc.contributor.referee2.fl_str_mv |
Frizzo, Clarissa Piccinin |
dc.contributor.referee2Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4757171J0 |
dc.contributor.referee3.fl_str_mv |
Fantinel, Leonardo |
dc.contributor.referee3Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4777461U9 |
dc.contributor.referee4.fl_str_mv |
Amaral, Simone Schneider |
dc.contributor.referee4Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4764345U8 |
dc.contributor.authorLattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4240255Z6 |
dc.contributor.author.fl_str_mv |
Lobo, Marcio Marçal |
contributor_str_mv |
Zanatta, Nilo Morel, Ademir Farias Frizzo, Clarissa Piccinin Fantinel, Leonardo Amaral, Simone Schneider |
dc.subject.por.fl_str_mv |
Cicloadição 1,3-dipolar Isoxazol Pirazol Nucleosídeo Celecoxib Regiosseletividade Trifluormetil-1H-pirazol |
topic |
Cicloadição 1,3-dipolar Isoxazol Pirazol Nucleosídeo Celecoxib Regiosseletividade Trifluormetil-1H-pirazol 1,3-dipolar cycloaddition Isoxazole Pyrazole Nucleoside Celecoxib Regioselectivity Trifluoromethyl-1H-pyrazole CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.eng.fl_str_mv |
1,3-dipolar cycloaddition Isoxazole Pyrazole Nucleoside Celecoxib Regioselectivity Trifluoromethyl-1H-pyrazole |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
This work reports the synthesis of a series of 29 new 1-(3-aryl-4,5-dihydroisoxazol-5-yl)methyl-4-trihalomethylpyrimidin-2(1H)-ones which have high pharmacological interest, since they are similar to natural and synthetic nucleosides. These compounds were obtained from 1,3-dippolar cycloaddition reaction between the 1-allyl-(6-aryl)-4-trihalomethylpyrimidin-2(1H)-ones and different benzonitrile oxides, obtained from the selected oximes of general formula ArCH=NOH (where Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, styryl, 2-OHC6H4 e 4-OHC6H4). The reaction conditions employed were highly regioselective, because it was observed the formation of only 3,5-substituted isomer by both NMR spectral analysis and X-ray diffractometry. The compounds were obtained in good yields (58 99%) and were purified from recrystallization or by column chromatography on silica gel. Some the obtained compounds showed antineoplastic activity in vitro against different tumor cell lines. Additionally, three new N3-substituted pyrimidinic dideoxynucleoside analogues were prepared, which were obtained in good yields (88 97%) from the reaction of N-allyl-2-methylthiopyrimidin-4(3H)-one and some of the benzonitrile oxides mentioned above. The reactions for the formation of N3-substituted nucleoside still require optimization. This thesis also described the regiochemisty controled synthesis of two series of pyrazoles, named 5(3)-aryl-3(5)-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides, structural analogues of Celecoxib (14 examples), where aryl = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, furan-2-yl, from the cyclocondensation reaction between 4-aryl-1,1,1-trifluoromethyl-4-methoxy-3-buten-2-ones and 4-hydrazinobenzenosulfonamide hydrochloride. The isolation of either isomer depended on the initial pH medium, where the alkaline pH favored the isolation of the 1,5-substituted isomer at yields of 73 99% and the reaction conducted in acid pH favored the isolation of the 1,3-substituted isomer, with yields of 77 94%. This study also allowed the isolation and spectroscopic characterization of a novel series of 3-aryl(heteroaryl)-5-hydroxy-5-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides (7 examples) in yields of 75 97% with interesting anti-inflammatory and antinociceptive activities in vivo. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-05-29 |
dc.date.accessioned.fl_str_mv |
2016-04-28 |
dc.date.available.fl_str_mv |
2016-04-28 |
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.citation.fl_str_mv |
LOBO, Marcio Marçal. Regioselective synthesis of Dideoxynucleosides and 3(5)-Trifluoromethyl-1H-pyrazoles of pharmacological interest. 2015. 298 f. Tese (Doutorado em Química) - Universidade Federal de Santa Maria, Santa Maria, 2015. |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/4276 |
identifier_str_mv |
LOBO, Marcio Marçal. Regioselective synthesis of Dideoxynucleosides and 3(5)-Trifluoromethyl-1H-pyrazoles of pharmacological interest. 2015. 298 f. Tese (Doutorado em Química) - Universidade Federal de Santa Maria, Santa Maria, 2015. |
url |
http://repositorio.ufsm.br/handle/1/4276 |
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por |
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por |
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100600000000 |
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dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Química |
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UFSM |
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Química |
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Universidade Federal de Santa Maria |
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