Liu_2014_Chem.Biol.Drug.Des_84_169

New dual binding site acetylcholinesterase (AChE) inhibitors have been designed and synthesized as a new drug candidate for the treatment of Alzheimer's disease (AD) through the binding to both catalytic and peripheral sites of the enzyme. Therefore, a series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives 6a-j were synthesized and investigated for their ability to inhibit the activity of human AChE (hAChE) in comparison with huperzine-A. All the compounds were found to inhibit AChE activity, especially compounds 6c and 6i with the inhibition value of 76.10% and 77.82%, respectively. The molecular docking study indicated that they were nicely accommodated by AChE. The molecular docking study revealed that 6c and 6i possessed a more optimal binding conformation than 6a and can perfectly fit into the active and peripheral site of hAChE, and consequently exhibited highly improved inhibitor potency to hAChE.