新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性
收稿日期: 2022-04-07
网络出版日期: 2022-05-12
基金资助
国家自然科学基金资助项目(21991080);国家自然科学基金资助项目(81602946);湖北省自然科学基金资助项目(2016CFB258)
Structure Characterization and Analgesic Activity of Novel Pyrazolo[3,4-d]pyrimidin-4-one Derivatives
Received date: 2022-04-07
Online published: 2022-05-12
本文以2-氰基-3-乙氧基丙烯酸乙酯与3,4-二甲基苯肼为原料，通过多步反应合成了三种新型吡唑并[3,4-d]嘧啶-4-酮类衍生物（A~C），通过核磁共振（NMR，包括1H NMR、13C NMR）和液相色谱-质谱联用（LC-MS）技术表征确证了其结构，并完整归属了三种化合物的1H NMR数据．对所合成的化合物1-(3,4-二甲基苯基)-6-甲基-5-[3-(哌啶-1-基)丙氧基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮（A），通过小鼠脑部质谱成像和福尔马林实验进行了初步的体内镇痛活性评价，我们发现化合物A能透过血脑屏障，并产生显著且剂量依赖的镇痛活性．本研究为以吡唑并[3,4-d]嘧啶-4-酮为骨架的镇痛药物的研发提供了结构和体内活性的基础研究数据．
关键词： 吡唑并[3,4-d]嘧啶-4-酮; 1H NMR; 13C NMR; 质谱成像; 镇痛活性
翟重钢 , 汪鹏程 , 单玉宝 , 兰昱 , 胡锐 , 杨运煌 . 新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性[J]. 波谱学杂志, 2023 , 40(1) : 1 -9 . DOI: 10.11938/cjmr20222995
Three compounds of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives (A~C) were synthesized through a multi-step reaction using ethyl-2-cyano-3-ethoxyacrylate and 3,4-dimethylphenylhydrazine. The structures of these compounds were identified by nuclear magnetic resonance (NMR, i.e., 1H NMR, 13C NMR), and liquid chromatography-mass spectrum (LC-MS), and the 1H NMR signals of each compound were fully assigned. The in vivo analgesic activity of synthesized compound A was preliminarily evaluated through mass spectrometry brain imaging and formalin induced pain model in mice. The imaging data and results showed that compound A could cross the blood-brain barrier and penetrate into the brain of mice, and produce a dose-dependent analgesic activity. This study provided a piece of fundamental research data on structural and in vivo activity for developing anti-pain drugs based on pyrazolo[3,4-d]pyrimidin-4-one scaffold.
| [1] | ABDELAZEEM A H, ABDELATEF S A, EL-SAADI M T, et al. Novel pyrazolopyrimidine derivatives targeting COXs and iNOS enzymes; design, synthesis and biological evaluation as potential anti-inflammatory agents[J]. Eur J Pharm Sci, 2014, 62: 197-211. |
| [2] | TAGELDIN G N, FAHMY S M, ASHOUR H M, et al. Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidine derivatives bearing thiazolidinone moiety as anti-inflammatory agents[J]. Bioorg Chem, 2018, 80: 164-173. |
| [3] | SEVERINA H I, GUBAR S M, BEZRUK I V, et al. Development and validation of hplc determination of related substances in a novel anticonvulsant agent epimidin[J]. Res J Pharm Tech, 2021, 14(6): 3223-3231. |
| [4] | WANG W, CHENG X, CUI X, et al. Synthesis and biological activity of novel Pyrazolo[3,4-d]pyrimidin-4-one derivatives as potent antifungal agent[J]. Pest Manag Sci, 2021, 77(7): 3529-3537. |
| [5] | RUSSO F, GUCCIONE S, ROMEO G, et al. Synthesis and pharmacological properties of pyrazolotriazolopyrimidine derivatives[J]. Eur J Med Chem, 1992, 27(1): 73-80. |
| [6] | 兰昱, 李景, 张伶莉, 等. 组胺H3受体拮抗剂/反向激动剂的研究与设计[C]// 南昌:中国药学会第十三届青年药学科研成果交流会, 2016, 239-246. |
| [7] | DOU F, CAO X, JING P, et al. Synthesis and evaluation of histamine H3 receptor ligand based on lactam scaffold as agents for treating neuropathic pain[J]. Bioorg Med Chem Lett, 2019, 29(12): 1492-1496. |
| [8] | LAZEWSKA D, BAJDA M, KALETA M, et al. Rational design of new multitarget histamine H3 receptor ligands as potential candidates for treatment of Alzheimer's disease[J]. Eur J Med Chem, 2020, 207: 112743. |
| [9] | ZHIDKOV M E, KUTKIN A V, FETISOVA E N, et al. Synthesis of new 1-(3,4-dimethylphenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin- 4-one derivatives[J]. Russian J Org Chem, 2017, 53(4): 592-598. |
| [10] | ABDELLATIF K R, ABDELALL E K, ABDELGAWAD M A, et al. Synthesis and anticancer activity of some new pyrazolo[3,4-d]pyrimidin-4-one derivatives[J]. Molecules, 2014, 19(3): 3297-3309. |
| [11] | DERMER O C. Metallic salts of alcohols and alcohol analogs[J]. Chem Rev, 1934, 14(3): 385-430. |
| [12] | WANG Z H, HU X, WANG T, et al. NMR spectroscopic studies on C-2 monosubstituted norbornene derivatives[J]. Chinese J Magn Reson, 2021, 38(3): 323-335. |
| [12] | 王子豪, 徐赫, 汪涛, 等. 外型和内型C-2位单取代降冰片烯衍生物的核磁共振波谱研究[J]. 波谱学杂志, 2021, 38(3): 323-335. |
| [13] | DOU M Y, ZHAO Q, HOU X L, et al. Structural elucidation and quantitative analysis of hydrogenation products of anthracene by NMR spectroscopy[J]. Chinese J Magn Reson, 2021, 38(2): 239-248. |
| [13] | 窦梦雨, 赵奇, 侯相林, 等. 蒽加氢产物的结构指认和定量核磁共振分析[J]. 波谱学杂志, 2021, 38(2): 239-248. |
| [14] | SHIBATA M, OHKUBO T, TAKAHASHI H, et al. Modified formalin test: characteristic biphasic pain response[J]. Pain, 1989, 38(3): 347-352. |
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