Abstract
A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC50 = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against HsAChE and was found to be even more active than donepezil and inhibited HsAChE better than EeAChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by memory loss and cognitive deficits
Five drugs have been approved by the United States Food and Drug Administration (FDA) for the symptomatic treatment of AD, four of which are acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, donepezil, and tacrine
We previously reported on the synthesis biological of a number of monomers multifunctional molecules derived from amyloid and precursor protein evaluation (APP) by secretases to form Aβ that will aggregate to toxic fibrils
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by memory loss and cognitive deficits. Five drugs have been approved by the United States Food and Drug Administration (FDA) for the symptomatic treatment of AD, four of which are acetylcholinesterase (AChE) inhibitors: rivastigmine, galantamine, donepezil, and tacrine These drugs prevent the action of cholinesterases (ChEs), which are responsible for the hydrolysis of the neurotransmitter acetylcholine (ACh), thereby increasing the levels of ACh in the brain and improving the cholinergic functions in AD patients [5,6]. Due to the multifactorial nature of AD, the development of compounds that could target generate multifunctional compounds targeting various hallmarks of AD, including BACE1 [16,17,18,19], different pathological features of the disease appears to be a viable research avenue.
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