Chromeno[3,4-b]xanthones as First-in-Class AChE and Aβ Aggregation Dual-Inhibitors
| Autor: | Hélio M. T. Albuquerque, Ana Oliveira, Pedro A. Fernandes, Artur M. S. Silva, Daniela Malafaia, Maria J. Ramos |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Amyloid
QH301-705.5 Aché Stereochemistry Xanthones Binding pocket chromeno[3 4-b]xanthones Article Catalysis Inorganic Chemistry chemistry.chemical_compound Catalytic triad Ic50 values Humans Biology (General) Physical and Theoretical Chemistry Aβ-aggregation QD1-999 Molecular Biology Spectroscopy Biological evaluation dual-target inhibitors Binding Sites Organic Chemistry General Medicine Acetylcholinesterase language.human_language Computer Science Applications Chemistry Neuroprotective Agents chemistry Drug development Chromones Chromone language AChE Cholinesterase Inhibitors Protein Multimerization Alzheimer’s disease Protein Binding |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 4145, p 4145 (2021) Volume 22 Issue 8 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22084145 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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