Donepezil-butylated hydroxytoluene (BHT) hybrids as Anti-Alzheimer's disease agents with cholinergic, antioxidant, and neuroprotective properties.

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.

journal_name

Eur J Med Chem

authors

Cai P,Fang SQ,Yang HL,Yang XL,Liu QH,Kong LY,Wang XB

doi

10.1016/j.ejmech.2018.08.005

subject

Has Abstract

pub_date

2018-09-05 00:00:00

pages

161-176

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30663-9

journal_volume

157

pub_type

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