Zeng Li-Yan, Liu Teng, Yang Jie, Yang Yueli, Cai Chun, Liu Shuwen
Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
Chemical Engineering College, Nanjing University of Science and Technology , Nanjing 210094, China.
ACS Comb Sci. 2017 Jul 10;19(7):437-446. doi: 10.1021/acscombsci.7b00016. Epub 2017 Jun 23.
A facile and versatile "on-water" protocol for the synthesis of pyrazolo[3,4-b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly synthesized and most of them were prepared in an hour. The scope and limitation indicated that electron withdrawing groups substituted on synthons, substituted benzoyl acetonitriles or aryl aldehydes, were helpful to construct the pyrazolo[3,4-b]pyridinones. The reaction media PEG2000/HO was successfully recycled and reused at least 5 times without any obvious decrease in yield. The anti-influenza activities of the derivatives were evaluated and the screening results highlighted two derivatives, which exhibited strong inhibitory activity against H5N1 pseudovirus. These positive bioassay results implied that the library of potential anti-influenza virus agent candidates could be rapidly prepared in an eco-friendly manner, and provided a new insight into drug discovery for medicinal chemists.
通过在一锅反应中前所未有的构建两个环和五个新键，开发了一种简便通用的“水相”合成吡唑并[3,4 - b]吡啶酮的方法。事实证明，水是该反应的重要促进剂，并且发现聚乙二醇2000（PEG2000）在产率方面能改善反应。新合成了32种衍生物，其中大部分在一小时内制备完成。反应范围和局限性表明，在合成子、取代苯甲酰乙腈或芳醛上取代的吸电子基团有助于构建吡唑并[3,4 - b]吡啶酮。反应介质PEG2000/水成功循环使用至少5次，产率没有明显下降。对这些衍生物的抗流感活性进行了评估，筛选结果突出了两种衍生物，它们对H5N1假病毒表现出强烈的抑制活性。这些积极的生物测定结果表明，可以以环保的方式快速制备潜在的抗流感病毒药物候选库，并为药物化学家的药物发现提供了新的思路。
