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Design, Synthesis, and Evaluation of 7H ‐thiazolo‐[3,2‐b]‐1,2,4‐triazin‐7‐one Derivatives as Dual Binding Site Acetylcholinesterase Inhibitors
Author(s) -
Liu Sijie,
Shang Ruofeng,
Shi Lanxiang,
Zhou Ran,
He Jingyu,
Wan David ChiCheong
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12362
Subject(s) - huperzine a , acetylcholinesterase , aché , docking (animal) , chemistry , stereochemistry , enzyme , binding site , active site , potency , biochemistry , in vitro , medicine , nursing
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 .