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A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2018-06-01 , DOI: 10.1016/j.bmcl.2018.05.063
Chamseddine Derabli , Imen Boualia , Ahmed B. Abdelwahab , Raouf Boulcina , Chawki Bensouici , Gilbert Kirsch , Abdelmadjid Debache

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.



中文翻译:

他克林-吡喃并吡唑衍生物的级联合成,体外胆碱酯酶的抑制活性和对接研究

在这项工作中,我们描述了一些用吡喃并吡唑部分修饰的新他克林类似物的制备。3- Fedländer缩合反应的3-甲基-1 H-吡唑-5(4 H)-一,芳基(或杂)醛,丙二腈和环己酮的一锅多组分反应生成标题化合物。为了寻找有效的胆碱酯酶抑制剂,在体外评估了该分子的合成杂环类似物的AChE和BChE抑制活性。大多数合成的化合物显示出显着的AChE抑制活性,IC 50值为0.044至5.80 µM,其中化合物5e5j被发现是最有效的抗AChE抑制剂,IC 50值分别为0.058和0.044 µM。AChE和BChE受体的分子模型模拟显示,IC 50值与停靠在其相关酶的活性位点的活性最高的抑制剂的结合相互作用模板之间具有良好的相关性。

更新日期:2018-06-01
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