Design, Synthesis and Evaluation of Novel Coumarin-Carbamate Hybrids as Acetylcholinesterase Inhibitors for Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly populations and is associated with the reduction of acetylcholine (ACh) neurotransmitter levels due to neuronal degeneration and acetylcholinesterase (AChE)-catalyzed hydrolysis. Thus, AChE inhibition represents a primary therapeutic target for AD treatment. Current first-line therapies for mild to moderate AD include acetylcholinesterase inhibitors (AChEIs) such as galantamine, donepezil, and rivastigmine. Donepezil inhibits AChE activity through interactions with the peripheral anionic site (PAS), thereby impeding amyloid-beta aggregation. Conversely, rivastigmine acts as a pseudo-irreversible inhibitor through carbamylation of the serine residue at the catalytic site (CS). In this study, we designed a novel series of compounds capable of pseudo-irreversibly inhibiting AChE while simultaneously interacting with the PAS. The coumarin nucleus was selected as the core structure for PAS interaction, with an additional carbamate group incorporated as the key functionality for carbamylation reactions at the CS. Specifically, 7-hydroxycoumarin was linked to a phenyl carbamate moiety using spacers of varying methylene units (2-7). Preliminary evaluations revealed that compound RKNU153 exhibited promising AChE inhibitory activity with 63.7% inhibition, and RKNU154 exhibited AChE inhibitory activity with 73.8% inhibition, at 100 mM concentration. However, carbamylation on the serine residue at the catalytic site of our compounds was not successful, being unable to engage in this critical interaction.