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杂环取代吡唑并[3,4-b]喹啉和苯并[b]吡唑并[4,3-g][1,8]萘啶衍生物的合成与药理学评价。

Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives.

机构信息

Research Institute for Medicines and Pharmaceutical Sciences, UL, Faculty of Pharmacy, University of Lisbon, Av Prof Gama Pinto, 1649-003 Lisbon, Portugal.

出版信息

Eur J Med Chem. 2011 Sep;46(9):4676-81. doi: 10.1016/j.ejmech.2011.05.068. Epub 2011 Jun 7.

DOI:10.1016/j.ejmech.2011.05.068
PMID:21715067
Abstract

The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H-benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC(50) (EeAChE) = 0.069 ± 0.006 μM; IC(50) (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K(i) = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.

摘要

报告了一系列吡唑并[3,4-b]喹啉和苯并[b]吡唑并[4,3-g][1,8]萘啶衍生物的合成和药理学分析。我们通过环己酮与易得的邻氨基-1-甲基-吡唑-二氰基的 Friedländer 型反应合成了不同取代的他克林类似物 1-6。生物评价表明，吡唑并他克林 1-6 是电鳗乙酰胆碱酯酶（EeAChE）的抑制剂，在微摩尔范围内，对血清马丁酰胆碱酯酶（eqBuChE）的抑制具有相当的选择性；最有趣的抑制剂是 N-（5-氨基-1-甲基-6,7,8,9-四氢-1H-苯并[b]吡唑并[4,3-g][1,8]萘啶-3-基）乙酰胺（5）[IC（50）（EeAChE）=0.069±0.006μM；IC（50）（eqBuChE）=6.3±0.6μM]。动力学研究表明，化合物 5 是 EeAChE 的混合型抑制剂（K（i）=155nM）。抑制剂 5 对鱼藤酮/寡霉素 A 诱导的神经元死亡表现出 45%的神经保护作用。

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