Design, synthesis and evaluation of new chromone-derived aminophosphonates as potential acetylcholinesterase inhibitor

A series of novel N-substituted α-aminophosphonates-bearing chromone moiety were synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities and antioxidant properties. Porcine pancreatic lipase was employed as a catalyst. Inhibitory activity against AChE ranged between 0.103 and 5.781 µM, whereas for BuChE, activities ranged between 8.619 and 18.789 µM. The results show that among the various synthesized compounds, strongest AChE inhibition was found for the compound containing aliphatic amine analogs, while in case of BuChE, aromatic amines showed better activity as compared to aliphatic amines. Compound 4j was found to be the most potent inhibitor of AChE with an IC 50 value of 0.103 ± 0.24 μM and inhibited AChE through mixed-type inhibition. Compound 4j was twofolds more potent than tacrine, 35-folds potent than galantamine and 50-folds potent than rivastigmine. Also, docking study revealed that compound 4j binds to both the peripheral anionic site and catalytic anionic site of AChE and BuChE. The antioxidant activities of synthesized compounds were performed against 2,2-diphenyl-1-picrylhydrazyl and hydrogen peroxide scavenging. DNA nicking activity of selected compounds also suggested that the compounds do not harm plasmid DNA pBR322. Compound 4j also showed significant DNA damage protection activity. Graphic abstract Novel N-substituted α-aminophosphonates bearing chromone moiety were synthesized and evaluated for anti-acetylcholinesterase, anti-butyrylcholinesterase, antioxidant and DNA damage activities.