title: 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.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University , 44, West Culture Road, Jinan, Shandong 250012, P. R. China.
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Xie
authors.forename: Dongqing
authors.initials: D
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.forename: Xiuli
authors.initials: X
authors.lastname: Ma
authors.forename: Wenbao
authors.initials: W
authors.lastname: Qi
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Shi
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053139:Oseltamivir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D053139:Oseltamivir; D009439:Neuraminidase; C535162:oseltamivir carboxylate