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三环吡唑并[1,5-c][1,3]苯并恶嗪-5(5H)-酮骨架作为选择性 BuChE 抑制剂的设计、合成与生物评价。

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

机构信息

a School of Pharmacy , Anhui Medical University , Hefei , PR China.

b Lujiang County People's Hospital , Lujiang , Anhui , PR China.

出版信息

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1506-1515. doi: 10.1080/14756366.2018.1488696.

DOI:10.1080/14756366.2018.1488696
PMID:30284486
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6179045/
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 (IC = 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 (K = 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.

摘要

基于三环支架作为丁酰胆碱酯酶 (BuChE) 抑制剂的结构分析，设计、合成了一系列吡唑并[1,5-c][1,3]苯并恶嗪-5(5H)-酮衍生物，并评估了它们对乙酰胆碱酯酶 (AChE) 和 BuChE 的抑制活性。具有 5-羰基和 7-或/和 9-卤素取代的化合物表现出潜在的 BuChE 抑制活性，其中化合物 6a、6c 和 6g 表现出最好的 BuChE 抑制作用 (IC = 1.06、1.63 和 1.63 μM)。构效关系表明，5-羰基和卤素取代基显著影响 BuChE 活性。发现化合物 6a 和 6g 无毒性、亲脂性，并表现出显著的神经保护活性和对 BuChE 的混合抑制作用 (K = 7.46 和 3.09 μM)。对接研究表明，化合物 6a 可以通过五个氢键、一个 Pi-Sigma 相互作用和三个 Pi-烷基相互作用被容纳到 BuChE 中。

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