Stereoisomers of oseltamivir - synthesis, in silico prediction and biological evaluation
Stereoisomers of oseltamivir - synthesis, in silico prediction and biological evaluation
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DOI：
10.1039/c6ob02673g
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发表时间：
2017-02-28
影响因子：
3.2
通讯作者：
Sebesta, Radovan
中科院分区：
文献类型：
--
作者：
Hajzer, Viktoria;Fisera, Roman;Sebesta, Radovan
奥司他韦是一种重要的抗病毒药物，其结构中具有三个手性中心。在八种可能的立体异构体中，迄今为止只合成和评价了两种。本文描述了奥司他韦的另外三个非对映异构体的立体选择性合成、计算活性预测和生物测试。这些异构体已被合成使用立体选择性有机催化迈克尔加成，环化和还原。通过量子化学计算评价了它们与甲型流感病毒神经氨酸酶N1的结合，并通过体外病毒抑制试验测试了它们的抗流感活性。所有三种异构体的抗病毒活性均低于奥司他韦，然而，奥司他韦的一种立体异构体（3S，4 R，5S）-异构体对达菲敏感的流感病毒株A/珀斯/265/2009（H5 N1）的体外效力与达菲相当。
Oseltamivir is an important antiviral drug, which possess three chirality centers in its structure. From eight possible stereoisomers, only two have been synthesized and evaluated so far. We describe herein the stereoselective synthesis, computational activity prediction and biological testing of another three diastereoisomers of oseltamivir. These isomers have been synthesized using stereoselective organocatalytic Michael addition, cyclization and reduction. Their binding to viral neuraminidase N1 of influenza A virus was evaluated by quantum-chemical calculations and their anti-influenza activities were tested by an in vitro virus-inhibition assay. All three isomers displayed antiviral activity lower than that of oseltamivir, however, one of the stereoisomers, (3S,4R,5S)-isomer, of oseltamivir showed in vitro potency towards the Tamiflu-sensitive influenza viral strain A/Perth/265/2009(H5N1) comparable to Tamiflu.