Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease

A series of benzoates (or phenylacetates or cinnamates) – tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2016-06, Vol.116, p.200-209
Main Authors: Zhang, Chao, Du, Qiao-Yi, Chen, Lang-Di, Wu, Wen-Hao, Liao, Si-Yan, Yu, Li-Hong, Liang, Xin-Tong
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Alzheimer Disease - drug therapy
Alzheimer's disease
Amyloid beta-Peptides - chemistry
Animals
Benzene - chemical synthesis
Benzene - chemistry
Benzene - pharmacology
Benzene - therapeutic use
Butyrylcholinesterase - metabolism
Chemistry Techniques, Synthetic
Cholinesterase inhibitors
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - pharmacology
Cholinesterase Inhibitors - therapeutic use
Drug Design
Kinetics
Models, Molecular
Multi-target-directed ligands
Peptide Fragments - chemistry
Protein Multimerization
Protein Structure, Secondary - drug effects
Self-induced Aβ aggregation
Tacrine
Tacrine - chemistry
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A series of benzoates (or phenylacetates or cinnamates) – tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Aβ aggregation with an IC50 value of 51.81 nM. A Lineweaver–Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure–activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity. [Display omitted] •15 novel tacrine derivatives were synthesized as multifunctional anti-AD agents.•Most of compounds showed excellent inhibition of AChE, BuChE and Aβ aggregation.•Most of compounds showed certain selectivity for AChE over BuChE.•The electron density of phenylacetate is the key to inhibitory activity of AChE.•Compound 7c was the best compound as out of the synthesized compounds.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.03.077