Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds
Simultaneous modulation of several targets or pathological events with a key pathogenic role is a promising strategy to tackle thus far difficult-to-cure or incurable multifactorial diseases, such as Alzheimer's disease (AD). In this scenario, multitarget compounds, i.e., single molecules that...
| Autores: | , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/165965 |
| Acceso en línea: | https://hdl.handle.net/2445/165965 |
| Access Level: | acceso abierto |
| Palabra clave: | Malaltia d'Alzheimer Malalties neurodegeneratives Química farmacèutica Alzheimer's disease Neurodegenerative Diseases Pharmaceutical chemistry |
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Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compoundsPérez Areales, Francisco JavierGarrido, MaríaAso Pérez, EsterBartolini, ManuelaDe Simone, AngelaEspargaró Colomé, AlbaGinex, TizianaSabaté Lagunas, RaimonPérez, BelénAndrisano, VincenzaLuque Garriga, F. XavierFerrer, Isidro (Ferrer Abizanda)Ciruela Alférez, FranciscoMesseguer i Peypoch, Àngel, 1946-Muñoz-Torrero López-Ibarra, DiegoMalaltia d'AlzheimerMalalties neurodegenerativesQuímica farmacèuticaAlzheimer's diseaseNeurodegenerative DiseasesPharmaceutical chemistrySimultaneous modulation of several targets or pathological events with a key pathogenic role is a promising strategy to tackle thus far difficult-to-cure or incurable multifactorial diseases, such as Alzheimer's disease (AD). In this scenario, multitarget compounds, i.e., single molecules that hit several targets, are superior to other multitarget strategies that are based on the use of more than one drug (drug cocktails, fixed-dose combinations), in terms of simpler drug development and better patient compliance, efficiency, and safety. In the frame of our research line devoted to the development of novel anti-AD drug candidates, we have recently prepared a new class of multitarget compounds, which were designed by combining pharmacophoric moieties of a known antioxidant agent (7-methoxy-2,2- dimethylchroman-6-ol (CR-6)) and an acetylcholinesterase (AChE) inhibitor (6-chlorotacrine), to primarily address two important pathological events of AD, namely oxidative stress and cholinergic deficit. Here, we present the synthesis of three short series of CR-6-chlorotacrine hybrids, featuring different linker functionalities (amide, inverse amide, or amine) and lengths, and their in vitro biological activities against AChE, butyrylcholinesterase, BACE-1, and β-amyloid and tau protein aggregation, their antioxidant activity, and BBB permeability. We will also show the results of the in vivo efficacy studies of two selected compounds in double transgenic APP/PS1 mice, a wellestablished mouse model of AD (behavioral studies, effects on amyloid pathology and oxidative stress).MDPI2019info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2445/165965Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaIngléshttps://doi.org/10.3390/proceedings2019022071MDPI Proceedings, 2019, vol. 22, p. 71https://doi.org/10.3390/proceedings2019022071cc-by (c) Pérez Areales, Francisco Javier et al., 2019http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1659652026-05-27T06:46:51Z |
| dc.title.none.fl_str_mv |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| title |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| spellingShingle |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds Pérez Areales, Francisco Javier Malaltia d'Alzheimer Malalties neurodegeneratives Química farmacèutica Alzheimer's disease Neurodegenerative Diseases Pharmaceutical chemistry |
| title_short |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| title_full |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| title_fullStr |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| title_full_unstemmed |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| title_sort |
Synthesis, in vitro profiling, and in vivo efficacy studies of a new family of multitarget anti-Alzheimer compounds |
| dc.creator.none.fl_str_mv |
Pérez Areales, Francisco Javier Garrido, María Aso Pérez, Ester Bartolini, Manuela De Simone, Angela Espargaró Colomé, Alba Ginex, Tiziana Sabaté Lagunas, Raimon Pérez, Belén Andrisano, Vincenza Luque Garriga, F. Xavier Ferrer, Isidro (Ferrer Abizanda) Ciruela Alférez, Francisco Messeguer i Peypoch, Àngel, 1946- Muñoz-Torrero López-Ibarra, Diego |
| author |
Pérez Areales, Francisco Javier |
| author_facet |
Pérez Areales, Francisco Javier Garrido, María Aso Pérez, Ester Bartolini, Manuela De Simone, Angela Espargaró Colomé, Alba Ginex, Tiziana Sabaté Lagunas, Raimon Pérez, Belén Andrisano, Vincenza Luque Garriga, F. Xavier Ferrer, Isidro (Ferrer Abizanda) Ciruela Alférez, Francisco Messeguer i Peypoch, Àngel, 1946- Muñoz-Torrero López-Ibarra, Diego |
| author_role |
author |
| author2 |
Garrido, María Aso Pérez, Ester Bartolini, Manuela De Simone, Angela Espargaró Colomé, Alba Ginex, Tiziana Sabaté Lagunas, Raimon Pérez, Belén Andrisano, Vincenza Luque Garriga, F. Xavier Ferrer, Isidro (Ferrer Abizanda) Ciruela Alférez, Francisco Messeguer i Peypoch, Àngel, 1946- Muñoz-Torrero López-Ibarra, Diego |
| author2_role |
author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malaltia d'Alzheimer Malalties neurodegeneratives Química farmacèutica Alzheimer's disease Neurodegenerative Diseases Pharmaceutical chemistry |
| topic |
Malaltia d'Alzheimer Malalties neurodegeneratives Química farmacèutica Alzheimer's disease Neurodegenerative Diseases Pharmaceutical chemistry |
| description |
Simultaneous modulation of several targets or pathological events with a key pathogenic role is a promising strategy to tackle thus far difficult-to-cure or incurable multifactorial diseases, such as Alzheimer's disease (AD). In this scenario, multitarget compounds, i.e., single molecules that hit several targets, are superior to other multitarget strategies that are based on the use of more than one drug (drug cocktails, fixed-dose combinations), in terms of simpler drug development and better patient compliance, efficiency, and safety. In the frame of our research line devoted to the development of novel anti-AD drug candidates, we have recently prepared a new class of multitarget compounds, which were designed by combining pharmacophoric moieties of a known antioxidant agent (7-methoxy-2,2- dimethylchroman-6-ol (CR-6)) and an acetylcholinesterase (AChE) inhibitor (6-chlorotacrine), to primarily address two important pathological events of AD, namely oxidative stress and cholinergic deficit. Here, we present the synthesis of three short series of CR-6-chlorotacrine hybrids, featuring different linker functionalities (amide, inverse amide, or amine) and lengths, and their in vitro biological activities against AChE, butyrylcholinesterase, BACE-1, and β-amyloid and tau protein aggregation, their antioxidant activity, and BBB permeability. We will also show the results of the in vivo efficacy studies of two selected compounds in double transgenic APP/PS1 mice, a wellestablished mouse model of AD (behavioral studies, effects on amyloid pathology and oxidative stress). |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/165965 |
| url |
https://hdl.handle.net/2445/165965 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
https://doi.org/10.3390/proceedings2019022071 MDPI Proceedings, 2019, vol. 22, p. 71 https://doi.org/10.3390/proceedings2019022071 |
| dc.rights.none.fl_str_mv |
cc-by (c) Pérez Areales, Francisco Javier et al., 2019 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc-by (c) Pérez Areales, Francisco Javier et al., 2019 http://creativecommons.org/licenses/by/3.0/es |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
MDPI |
| publisher.none.fl_str_mv |
MDPI |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona |
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Universidad de Barcelona |
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Dipòsit Digital de la UB |
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Dipòsit Digital de la UB |
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