Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
33838585
DOI
10.1016/j.ejmech.2021.113397
PII: S0223-5234(21)00246-4
Knihovny.cz E-zdroje
- Klíčová slova
- Alzheimer’s disease, Aβ aggregation, BACE1, Butyrylcholinesterase, GABA transporters, Inhibitors, Multifunctional ligands,
- MeSH
- Alzheimerova nemoc farmakoterapie metabolismus MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- neuroprotektivní látky chemická syntéza chemie farmakologie MeSH
- objevování léků * MeSH
- proteiny přenášející GABA přes plazmatickou membránu metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- butyrylcholinesterasa MeSH
- cholinesterasové inhibitory MeSH
- neuroprotektivní látky MeSH
- proteiny přenášející GABA přes plazmatickou membránu MeSH
Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 μM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC50 = 10.96 μM; and mGAT2 IC50 = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 μM and IC50 = 2.95 μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.
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