Design, Synthesis, and Evaluation of 7H ‐thiazolo‐[3,2‐b]‐1,2,4‐triazin‐7‐one Derivatives as Dual Binding Site Acetylcholinesterase Inhibitors

New dual binding site acetylcholinesterase ( AC h E ) inhibitors have been designed and synthesized as a new drug candidate for the treatment of A lzheimer'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 AC h E ( h AChE ) in comparison with huperzine‐A. All the compounds were found to inhibit AC h E 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 AC h E . 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 h AChE , and consequently exhibited highly improved inhibitor potency to h AChE .