Design,synthesis and biological evaluation of tricyclic pyrazolo[1,5-c][1,3]benzoxazin-5(5H)-one scaffolds as selective BuChE inhibitors |
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Authors: | Guo-Liang Qiu Shao-Sheng He Shi-Chao Chen Bo Li Hui-Hui Wu |
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Institution: | 1. School of Pharmacy, Anhui Medical University, Hefei, PR China;2. Lujiang County People's Hospital, Lujiang, Anhui, PR China;3. Anhui Prevention and Treatment Center for Occupational Disease, Hefei, PR China |
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Abstract: | Based on the structural analysis of tricyclic scaffolds as butyrylcholinesterase (BuChE) inhibitors, a series of pyrazolo1,5-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. |
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Keywords: | acetylcholinesterase butyrylcholinesterase pyrazolo[1 5-c][1 3]benzoxazin-5(5H)-one tricyclic scaffold Alzheimer’s disease |
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