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

作者：Qiu, Guo-Liang; He, Shao-Sheng; Chen, Shi-Chao; Li, Bo; Wu, Hui-Hui; Zhang, Jing^*; Tang, Wen-Jian^*

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, 33(1): 1506-1515.

DOI：10.1080/14756366.2018.1488696

• acetylcholinesterase
• butyrylcholinesterase
• pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one
• tricyclic scaffold
• Alzheimer's disease

Based on the structural analysis of tricyclic scaffolds as butyrylcholinesterase (BuChE) inhibitors, a series of pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-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 compounds 6a, 6c and 6g showed the best BuChE inhibition (IC50 = 1.06, 1.63 and 1.63 mu M, respectively). The structure-activity relationship showed that the 5-carbonyl and halogen substituents significantly influenced BuChE activity. Compounds 6a and 6g were found nontoxic, lipophilic and exhibited remarkable neuroprotective activity and mixed-type inhibition against BuChE (K-i=7.46 and 3.09 mu M, respectively). Docking studies revealed that compound 6a can be accommodated into BuChE via five hydrogen bonds, one Pi-Sigma interaction and three Pi-Alkyl interactions.

• 出版日期2018-10-4
• 单位安徽医科大学