Design, synthesis and biological evaluation of tricyclic pyrazolo[1, 5-c][1, 3]benzoxazin-5(5H)-one scaffolds as selective BuChE inhibitors. (1st January 2018)

• Record Type: Journal Article
• Authors: Qiu, Guo-Liang; He, Shao-Sheng; Chen, Shi-Chao; Li, Bo; Wu, Hui-Hui; Zhang, Jing; Tang, Wen-Jian
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 33:Number 1(2018)
• Page Start: 1506
• Page End: 1515
• Publication Date: 2018-01-01
• Subjects: acetylcholinesterase -- butyrylcholinesterase -- pyrazolo[1, 5-c][1, 3]benzoxazin-5(5H)-one -- tricyclic scaffold -- Alzheimer's disease; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2018.1488696
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Based on the structural analysis of tricyclic scaffolds as butyrylcholinesterase (BuChE) inhibitors, a series of pyrazolo[1, 5- c ][1, 3]benzoxazin-5(5 H )-one derivatives were designed, synthesized and evaluated for their acetylcholinesterase (AChE) and BuChE inhibitory activity. Compounds with 5-carbonyl and 7- or/and 9-halogen substitutions showed potential BuChE inhibitory activity, among which compounds6a, 6c and6g showed the best BuChE inhibition (IC50 = 1.06, 1.63 and 1.63 µM, respectively). The structure–activity relationship showed that the 5-carbonyl and halogen substituents significantly influenced BuChE activity. Compounds6a and6g were found nontoxic, lipophilic and exhibited remarkable neuroprotective activity and mixed-type inhibition against BuChE ( K i = 7.46 and 3.09 µM, respectively). Docking studies revealed that compound6a can be accommodated into BuChE via five hydrogen bonds, one Pi–Sigma interaction and three Pi–Alkyl interactions.