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.
Highlights
Alzheimer’s disease (AD), characterized by progressive deterioration of memory and other cognitive impairments, is a chronic neurodegenerative disease1,2
Chemistry According to recent works37–39, pyrazolo[1,5-c][1,3]benzoxazepin5(5H)-one scaffolds (3a–3f and 6a–6q, as shown in Table 1) were synthesized by the protocol outlined in Schemes 1 and 2
The intermediate 2-pyrazolines (2 and 5) were synthesized through the cyclization reaction of excess hydrazine hydrate with the styrene ketones, which were obtained from Claisen–Schmidt condensation
Summary
Alzheimer’s disease (AD), characterized by progressive deterioration of memory and other cognitive impairments, is a chronic neurodegenerative disease. One efficient approach to treat AD is to restore the level of acetylcholine using cholinesterases (ChEs), such as acetylcholinesterase (AChE) and butyrlcholinesterase (BuChE) inhibitors. It has been found that amyloid protein plaques can be caused by ChEs and can be decreased by ChEs inhibitors. In view of an increased level of BuChE and decreased level of AChE in the progressed AD, development of effective and selective BuChE inhibitor is of vital importance. There are some types of scaffolds with BuChE inhibition, selective BuChE inhibitors are far from abundance. Several pyrazole-containing motifs were designed as potential telomerase inhibitors with anticancer activity, selective monoamine oxidase and/or ChE inhibitors for treating Alzheimer’s and Parkinson’s diseases. A series of pyrazole-containing tricyclic scaffolds were found as selective BuChE inhibitors. We synthesized a series of pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one derivatives, and evaluated for their cholinesterase inhibitory activity and the active compounds were used to study the preliminary mechanism
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