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

Abstract

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 µM, 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 (Ki = 7.46 and 3.09 µM, 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.

Keywords

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