Liu, Y;
Uras, G;
Onuwaje, I;
Li, W;
Yao, H;
Xu, S;
Li, X;
... Xu, J; + view all
(2022)
Novel inhibitors of AChE and Aβ aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease.
European Journal of Medicinal Chemistry
, 235
, Article 114305. 10.1016/j.ejmech.2022.114305.
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EJMC 2022 - 24R anti-AD - accepted version.pdf - Accepted Version Download (2MB) | Preview |
Abstract
A series of sulfone analogs of donepezil were designed and synthesized as novel acetylcholinesterase (AChE) inhibitors with the potent inhibiting Aβ aggregation and providing neuroprotective effects as potential modalities for Alzheimer's disease (AD). Most of the target compounds displayed effective inhibition of AChE, especially compound 24r which displayed powerful inhibitory activity (IC50 = 2.4 nM). Kinetic and docking studies indicated that compound 24r was a mixed-type inhibitor. Furthermore, in glyceraldehyde (GA)-exposed SH-SY5Y differentiated neuronal cells, compound 24r could potently inhibit AChE, reduce tau phosphorylation at S396 residue, provide neuroprotection by rescuing neuronal morphology and increasing cell viability. It was also found to reduce amyloid aggregation in the presence of AChE. In addition, compound 24r showed evident protections from mitochondrial membrane dysfunction and oxidative stress in okadaic acid-induced pharmacological models. Moreover, compound 24r exhibited more effective treatment prospects in vivo than donepezil, including a moderate blood-brain barrier permeability, a more potent AChE inhibitory activity and behavioral improvement in scopolamine-induced cognition-impaired mice model at a much lower dose. Collectively, compound 24r is a promising lead compound for further investigation to discovery and development of new anti-AD agents.
| Type: | Article |
|---|---|
| Title: | Novel inhibitors of AChE and Aβ aggregation with neuroprotective properties as lead compounds for the treatment of Alzheimer's disease |
| Location: | France |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ejmech.2022.114305 |
| Publisher version: | https://doi.org/10.1016/j.ejmech.2022.114305 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | AChE inhibitor, Alzheimer's disease, Donepezil, Inhibiting Aβ aggregation, Neuroprotection, Sulfone group, Acetylcholinesterase, Alzheimer Disease, Amyloid beta-Peptides, Animals, Cholinesterase Inhibitors, Donepezil, Lead, Mice, Neuroprotection, Neuroprotective Agents, Structure-Activity Relationship |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10148558 |
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