Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- Alzheimer’s disease, Aβ aggregation, BACE-1 inhibitors, butyrylcholinesterase inhibitors, molecular docking, multifunctional agents, tau aggregation,
- MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- Amyloid beta-Peptides drug effects metabolism MeSH
- Butyrylcholinesterase pharmacology MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Humans MeSH
- Peptide Fragments metabolism MeSH
- tau Proteins drug effects MeSH
- Drug Design * MeSH
- Molecular Docking Simulation methods MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amyloid beta-Peptides MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Peptide Fragments MeSH
- tau Proteins MeSH
The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.
References provided by Crossref.org
Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease
