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 (IC 50, 0.075 μM for ee AChE and 0.75 μM for h AChE) and Monoamine oxidase B (MAO-B) inhibition (IC 50 , 7.4 μM for h MAO-B), excellent antioxidant activity (71.7 μM of IC 50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, h AChE-induced A β aggregation. Moreover, 7d possessed neuroprotective potency against H 2 O 2 -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. Graphical abstract Image 1 Highlights • A series of donepezil-BHT derivatives through two modifications were rational designed, synthesized and evaluated. • Most of the compounds showed good inhibitory activities against AChE and MAO-B as well as remarkable antioxidant activities. • 7d displayed a balanced multifunctional profile covering an intriguing AChE and MAO-B inhibition, antioxidant activity. • 7d possessed neuroprotection against H 2 O 2 -induced oxidative damage and LPS-stimulated inflammation on cell level. • 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity and hepatotoxicity. [ABSTRACT FROM AUTHOR]