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Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease.
Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2021 Nov; Vol. 116, pp. 105387. Date of Electronic Publication: 2021 Oct 04. - Publication Year :
- 2021
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Abstract
- Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an β-amyloid (Aβ) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Aβ <subscript>1-42</subscript> aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Aβ <subscript>1-42</subscript> pentamers. Moreover, 13a effectively attenuated Aβ <subscript>1-42</subscript> oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Acetylcholinesterase metabolism
Alzheimer Disease metabolism
Amines chemistry
Amyloid beta-Peptides antagonists & inhibitors
Amyloid beta-Peptides metabolism
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors chemistry
Dose-Response Relationship, Drug
Humans
Ligands
Molecular Structure
Neuroprotective Agents chemical synthesis
Neuroprotective Agents chemistry
Peptide Fragments antagonists & inhibitors
Peptide Fragments metabolism
Picolinic Acids chemistry
Protein Aggregates drug effects
Structure-Activity Relationship
Tacrine chemistry
Alzheimer Disease drug therapy
Amines pharmacology
Cholinesterase Inhibitors pharmacology
Drug Design
Neuroprotective Agents pharmacology
Picolinic Acids pharmacology
Tacrine pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 116
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34628225
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105387