Abstract
Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM). Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE) (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM), and it inhibits amyloid beta aggregation (35.8% at 10 μM). Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB) was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.
Highlights
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder and the most frequent cause of dementia
Two series of compounds were designed as dual binding site acetylcholinesterase inhibitors based on our previous research
EeAChE inhibitory potency, 10%, compound defined as not active; Data from ref. [37] for compound I and from [40] for compound a IC50 values are expressed as mean ± standard error of the mean (SEM) of at least three experiments; f % of inhibition of we found that the replacement diethylamine
Summary
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder and the most frequent cause of dementia. World Health Organization estimates the global prevalence of the disease at 36 million [1]. Annual costs at $604 billion [2]. These figures are expected to rise, yet we have no new drugs to ease the burden of the disease. An alarmingly low number of drug candidates are undergoing clinical trials, with only a dozen compounds in Phase III [3,4]. These facts highlight the necessity of new effective therapeutic agents for AD
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