One-step microwave enhanced synthesis, biological evaluation, and molecular modeling investigations of donepezil analogs as acetylcholinesterase inhibitors

Acetylcholinesterase (AChE) is an important enzyme that hydrolyzes the neurotransmitter acetylcholine. Inhibiting AChE represents one of the therapeutic strategies for treating the symptoms of Alzheimer’s disease (AD). To date, only several AD drugs have been approved by the U.S. Food and Drug Administration, with donepezil being the most commonly used. In this study, we synthesized 46 donepezil-based analogs via a one-step microwave-assisted synthetic route and evaluated them in vitro using an AChE inhibition assay in order to better understand structural requirements important for the inhibition. Our structure-activity relationship studies revealed that various halogens, electron-withdrawing, and electron-donating groups placed in the ortho- and meta- positions on the phenyl moiety of donepezil are generally well-tolerated, yielding potent AChE inhibitors in the low nanomolar range similar to donepezil, while polysubstitutions led to moderate or significant decreases in inhibition potency.