Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

Jian Zhang, Natarajan Arul Murugan, Ye Tian, Chiara Bertagnin, Zengjun Fang, Dongwei Kang, Xiujie Kong, Haiyong Jia, Zhuosen Sun, Ruifang Jia, Ping Gao, Vasanthanathan Poongavanam, Arianna Loregian, Wenfang Xu, Xiuli Ma, Xiao Ding, Bing Huang, Peng Zhan, Xinyong Liu

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Abstract

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume61
Issue number22
Pages (from-to)9976-9999
ISSN0022-2623
DOIs
Publication statusPublished - 2018

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