Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/230226 |
Resumo: | Cholinesterase enzymes are important targets for the therapy of Alzheimer’s disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo- and heterodimers of bis(7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo- and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds. |
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Lopes, João Paulo BizarroCosta, Jessie Sobieski daCeschi, Marco AntonioGoncalves, Carlos Alberto SaraivaKonrath, Eduardo LuisKarl, Ana Luiza MartinsGuedes, Isabella AlvimDardenne, Laurent Emmanuel2021-09-24T04:23:08Z20170103-5053http://hdl.handle.net/10183/230226001051310Cholinesterase enzymes are important targets for the therapy of Alzheimer’s disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo- and heterodimers of bis(7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo- and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds.application/pdfengJournal of the Brazilian Chemical Society. Vol. 28, n. 11 (2017), p. 2218-2228ColinesterasesDoença de AlzheimerBistacrineChiralCholinesterasesSynthesisMolecular dockingChiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approachinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/otherinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001051310.pdf.txt001051310.pdf.txtExtracted Texttext/plain44211http://www.lume.ufrgs.br/bitstream/10183/230226/2/001051310.pdf.txtbc3decd3b28cf5a050629e1b15538164MD52ORIGINAL001051310.pdfTexto completo (inglês)application/pdf3157228http://www.lume.ufrgs.br/bitstream/10183/230226/1/001051310.pdffcac320eab8114a8ef3c2203d654b6bdMD5110183/2302262021-10-04 04:26:24.341783oai:www.lume.ufrgs.br:10183/230226Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2021-10-04T07:26:24Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
title |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
spellingShingle |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach Lopes, João Paulo Bizarro Colinesterases Doença de Alzheimer Bistacrine Chiral Cholinesterases Synthesis Molecular docking |
title_short |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
title_full |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
title_fullStr |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
title_full_unstemmed |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
title_sort |
Chiral bistacrine analogues : synthesis, cholinesterase inhibitory activity and a molecular modeling approach |
author |
Lopes, João Paulo Bizarro |
author_facet |
Lopes, João Paulo Bizarro Costa, Jessie Sobieski da Ceschi, Marco Antonio Goncalves, Carlos Alberto Saraiva Konrath, Eduardo Luis Karl, Ana Luiza Martins Guedes, Isabella Alvim Dardenne, Laurent Emmanuel |
author_role |
author |
author2 |
Costa, Jessie Sobieski da Ceschi, Marco Antonio Goncalves, Carlos Alberto Saraiva Konrath, Eduardo Luis Karl, Ana Luiza Martins Guedes, Isabella Alvim Dardenne, Laurent Emmanuel |
author2_role |
author author author author author author author |
dc.contributor.author.fl_str_mv |
Lopes, João Paulo Bizarro Costa, Jessie Sobieski da Ceschi, Marco Antonio Goncalves, Carlos Alberto Saraiva Konrath, Eduardo Luis Karl, Ana Luiza Martins Guedes, Isabella Alvim Dardenne, Laurent Emmanuel |
dc.subject.por.fl_str_mv |
Colinesterases Doença de Alzheimer |
topic |
Colinesterases Doença de Alzheimer Bistacrine Chiral Cholinesterases Synthesis Molecular docking |
dc.subject.eng.fl_str_mv |
Bistacrine Chiral Cholinesterases Synthesis Molecular docking |
description |
Cholinesterase enzymes are important targets for the therapy of Alzheimer’s disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo- and heterodimers of bis(7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedländer cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo- and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds. |
publishDate |
2017 |
dc.date.issued.fl_str_mv |
2017 |
dc.date.accessioned.fl_str_mv |
2021-09-24T04:23:08Z |
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http://hdl.handle.net/10183/230226 |
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0103-5053 |
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001051310 |
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http://hdl.handle.net/10183/230226 |
dc.language.iso.fl_str_mv |
eng |
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eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
Journal of the Brazilian Chemical Society. Vol. 28, n. 11 (2017), p. 2218-2228 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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