Synthesis, biological evaluation, and molecular dynamics of novel coumarin based phosphorothioates as cholinesterase inhibitors

Abstract

Inhibition of acetylcholinesterase has been validated as an effective target for treatment of Alzheimer's disease by increasing the levels of acetylcholine and improving the communication between the neuronal cells. Literature reports revealed that coumarins and phosphorothioates were shown to be promising scaffolds as acetylcholinesterase inhibitors. A series of novel chroman-4one derivative moieties (6a-6d, 7b-7d, 8–11) were synthesized with good to excellent yield by reactions of coumarin sulfonyl chlorides 1a, b with various di- and trialkylphosphites, Wittig reagents 4a-d, and the new products were evaluated for their cholinesterase (ChE) inhibitory activities. Structure–activity relationship study results showed that 7a is the most potent compound (anti AChE activity; IC50 = 0.73 μg/ ml), indicating the preference for hydrophobic interaction and Pi-stacked at the side chain of the molecule. This was supported further by molecular docking and dynamics studies of the most potent compound (7a against AChE), which revealed favored interactions with the ChE enzyme's binding pockets.