Discovery of N-Substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase

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• 作者：Yuanchao Xie ; Dongqing Xu ; Bing Huang ; Xiuli Ma ; Wenbao Qi ; Fangyuan Shi ; Xinyong Liu ; Yingjie Zhang ; Wenfang Xu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8445-8458
• 全文大小：679K
• ISSN：1520-4804

文摘

To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC₅₀ values of 0.0019, 0.0038, and 0.0067 渭M against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.