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Donepezil-butylated hydroxytoluene (BHT) hybrids as Anti-Alzheimer's disease agents with cholinergic, antioxidant, and neuroprotective properties
- Source :
- European Journal of Medicinal Chemistry. 157:161-176
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC50, 0.075 μM for eeAChE and 0.75 μM for hAChE) and Monoamine oxidase B (MAO-B) inhibition (IC50, 7.4 μM for hMAO-B), excellent antioxidant activity (71.7 μM of IC50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, hAChE-induced Aβ aggregation. Moreover, 7d possessed neuroprotective potency against H2O2-induced oxidative damage on PC12 cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD.
- Subjects :
- 0301 basic medicine
Antioxidant
DPPH
medicine.medical_treatment
Cholinergic Agents
Pharmacology
PC12 Cells
Antioxidants
Cell Line
Mice
Protein Aggregates
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Piperidines
Alzheimer Disease
Drug Discovery
medicine
Animals
Butylated hydroxytoluene
Donepezil
Amyloid beta-Peptides
ABTS
Dose-Response Relationship, Drug
Molecular Structure
Organic Chemistry
General Medicine
Butylated Hydroxytoluene
Acetylcholinesterase
Rats
Neuroprotective Agents
030104 developmental biology
chemistry
Indans
Cholinesterase Inhibitors
Trolox
Monoamine oxidase B
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 157
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....feffae6f15e13faf2fa68a74f455b139