Synthesis, In Vitro Profiling, and In Vivo Efficacy Studies of a New Family of Multitarget Anti-Alzheimer Compounds †
by
,
Francisco Javier Pérez-Areales
1,*, 
María Garrido
2,
Ester Aso
3,4,
Manuela Bartolini
5,
Angela De Simone
6,
Alba Espargaró
7,
Tiziana Ginex
8,
Raimon Sabate
7,
Belén Pérez
9,
Vincenza Andrisano
6,
Francisco Javier Luque
8,
Isidro Ferrer
3,
Francisco Ciruela
4,
Angel Messeguer
2 and
Diego Muñoz-Torrero
1 1
Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
2
Department of Biological Chemistry and Molecular Modeling, Instituto de Química Avanzada de Catalunya (IQAC-CSIC), C/Jordi Girona, 18-26, E-08034 Barcelona, Spain
3
Pathological Anatomy Unit, Pathology and Experimental Therapeutics Department, IDIBELL, and Neurosciencies Institute, University of Barcelona, and Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), E-08907 L’Hospitalet de Llobregat, Spain
4
Pharmacology Unit, Pathology and Experimental Therapeutics Department, IDIBELL, and Neurosciencies Institute, University of Barcelona, E-08907 L’Hospitalet de Llobregat, Spain
5
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
6
Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, I-47921 Rimini, Italy
7
Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
8
Department of Nutrition, Food Sciences and Gastronomy, Faculty of Pharmacy and Food Sciences (Campus Torribera), and IBUB, University of Barcelona, Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain
9
Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Spain
*
Author to whom correspondence should be addressed.
†
Presented at the 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in
Drug Discovery, Barcelona, Spain, 15–17 May 2019.
Proceedings 2019, 22(1), 71; https://doi.org/10.3390/proceedings2019022071
Published: 14 August 2019
(This article belongs to the Proceedings of The 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in Drug Discovery)
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 well-established mouse model of AD (behavioral studies, effects on amyloid pathology and oxidative stress).
References
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MDPI and ACS Style
Pérez-Areales, F.J.; Garrido, M.; Aso, E.; Bartolini, M.; Simone, A.D.; Espargaró, A.; Ginex, T.; Sabate, R.; Pérez, B.; Andrisano, V.; et al. Synthesis, In Vitro Profiling, and In Vivo Efficacy Studies of a New Family of Multitarget Anti-Alzheimer Compounds. Proceedings 2019, 22, 71. https://doi.org/10.3390/proceedings2019022071
AMA Style
Pérez-Areales FJ, Garrido M, Aso E, Bartolini M, Simone AD, Espargaró A, Ginex T, Sabate R, Pérez B, Andrisano V, et al. Synthesis, In Vitro Profiling, and In Vivo Efficacy Studies of a New Family of Multitarget Anti-Alzheimer Compounds. Proceedings. 2019; 22(1):71. https://doi.org/10.3390/proceedings2019022071
Chicago/Turabian StylePérez-Areales, Francisco Javier, María Garrido, Ester Aso, Manuela Bartolini, Angela De Simone, Alba Espargaró, Tiziana Ginex, Raimon Sabate, Belén Pérez, Vincenza Andrisano, and et al. 2019. "Synthesis, In Vitro Profiling, and In Vivo Efficacy Studies of a New Family of Multitarget Anti-Alzheimer Compounds" Proceedings 22, no. 1: 71. https://doi.org/10.3390/proceedings2019022071
