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
文献类型： 外文期刊
作者： Zhang, Jian 1 ; Murugan, Natarajan Arul 2 ; Tian, Ye 1 ; Bertagnin, Chiara 4 ; Fang, Zengjun 1 ; Kang, Dongwei 1 ; Kon 1 ;
作者机构： 1.Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China
2.KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden
3.Shandong Univ, Sch Basic Med Sci, Dept Immunol, Key Lab Expt Teratol,Minist Educ,Key Lab Infect &, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China
4.Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy
5.Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China
6.Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark
7.Shandong Univ, Hosp 2, 247 Beiyuan Ave, Jinan 250033, Shandong, Peoples R China
8.Uppsala Univ, Dept Chem, Biomed Ctr BMC, Husargatan 3, S-75237 Uppsala, Sweden
期刊名称：JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：7.446； 五年影响因子：7.319 ）
ISSN： 0022-2623
年卷期： 2018 年 61 卷 22 期
页码：
收录情况： SCI
摘要： 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 HSN1, 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.
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