Discovery of N-substituted oseltamivir derivatives as potent and selective inhibitors of H5N1 influenza neuraminidase.

Abstract

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 μM 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.

• Authors: Yuanchao Xie, Dongqing Xu, Bing Huang, Xiuli Ma, Wenbao Qi, Fangyuan Shi, Xinyong Liu, Yingjie Zhang, Wenfang Xu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 20 Pg. 8445-58 (Oct 23 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25255388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Viral Proteins
• Oseltamivir
• Neuraminidase
• oseltamivir carboxylate

Topics

• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Binding Sites
• Chemistry Techniques, Synthetic
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Influenza A Virus, H5N1 Subtype (drug effects, enzymology)
• Inhibitory Concentration 50
• Molecular Docking Simulation
• Neuraminidase (antagonists & inhibitors, genetics, metabolism)
• Oseltamivir (analogs & derivatives, chemistry, pharmacology)
• Structure-Activity Relationship
• Viral Proteins (antagonists & inhibitors, metabolism)