6-Acetyl-5H-thiazolo[3,2-a]pyrimidine Derivatives as the Novel Acetylcholinesterase Inhibitors: Design, Synthesis, and Biological Activity

Hui      Zhi; Can      Zhang; Zhixin      Cheng; Zhe      Jin; Erfang      Huang; Shuo      Li; Huangquan      Lin; David   Chicheong   Wan; Chun      Hu

doi:10.2174/1573406411309050010

Abstract

Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer’s drugs. A series of 6-acetyl- 5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors were designed based on virtual screening methods. The target compounds which are not reported in the literature were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, 1H-NMR and 13C-NMR. The biological evaluation against human acetylcholinesterase in vitro showed most of the target compounds exhibited varying inhibition at 10 µM using the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer’s disease, and a foundation in search for improved acetylcholinesterase inhibitors with the novel scaffolds. The preliminary structure-activity relationships were the 2-hydroxyethoxy group at the phenyl ring at C4 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds.

Keywords: Acetylcholinesterase inhibitor, 6-Acetyl-5H-thiazolo[3, 2-a]pyrimidine derivatives, Biological activity, Docking screening, Heterocycles, Synthesis.

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