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Article

Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors

1
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
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LAQV-REQUIMTE, Computational Biochemistry Laboratory, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
*
Authors to whom correspondence should be addressed.
Academic Editor: Philippe De Deurwaerdère
Int. J. Mol. Sci. 2021, 22(8), 4145; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084145
Received: 2 March 2021 / Revised: 13 April 2021 / Accepted: 14 April 2021 / Published: 16 April 2021
(This article belongs to the Section Molecular Pharmacology)
Alzheimer’s disease (AD) is a complex multifactorial disorder, mainly characterized by the progressive loss of memory and cognitive, motor, and functional capacity. The absence of effective therapies available for AD alongside the consecutive failures in the central nervous system (CNS) drug development has been motivating the search for new disease-modifying therapeutic strategies for this disease. To address this issue, the multitarget directed ligands (MTDLs) are emerging as a therapeutic alternative to target the multiple AD-related factors. Following this concept, herein we describe the design, synthesis, and biological evaluation of a family of chromeno[3,4-b]xanthones as well as their (E)-2-[2-(propargyloxy)styryl]chromone precursors, as first-in-class acetylcholinesterase (AChE) and β-amyloid (Aβ) aggregation dual-inhibitors. Compounds 4b and 10 emerged as well-balanced dual-target inhibitors, with IC50 values of 3.9 and 2.9 μM for AChE and inhibitory percentages of 70 and 66% for Aβ aggregation, respectively. The molecular docking showed that most of the compounds bound to AChE through hydrogen bonds with residues of the catalytic triad and π-stacking interactions between the main scaffold and the aromatic residues present in the binding pocket. The interesting well-balanced activities of these compounds makes them interesting templates for the development of new multitarget compounds for AD. View Full-Text
Keywords: Alzheimer’s disease; AChE; Aβ-aggregation; dual-target inhibitors; chromeno[3,4-b]xanthones Alzheimer’s disease; AChE; Aβ-aggregation; dual-target inhibitors; chromeno[3,4-b]xanthones
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MDPI and ACS Style

Malafaia, D.; Oliveira, A.; Fernandes, P.A.; Ramos, M.J.; Albuquerque, H.M.T.; Silva, A.M.S. Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors. Int. J. Mol. Sci. 2021, 22, 4145. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084145

AMA Style

Malafaia D, Oliveira A, Fernandes PA, Ramos MJ, Albuquerque HMT, Silva AMS. Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors. International Journal of Molecular Sciences. 2021; 22(8):4145. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084145

Chicago/Turabian Style

Malafaia, Daniela, Ana Oliveira, Pedro A. Fernandes, Maria J. Ramos, Hélio M.T. Albuquerque, and Artur M.S. Silva 2021. "Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors" International Journal of Molecular Sciences 22, no. 8: 4145. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084145

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