Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and-2 Influenza A Neuraminidases, Including a Drug-Resistant Variant
文献类型： 外文期刊
作者： Zhang, Jian 1 ; Poongavanam, Vasanthanathan 2 ; Kang, Dongwei 1 ; Bertagnin, Chiara 4 ; Lu, Huamei 3 ; Kong, Xiujie 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.Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark
3.Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China
4.Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy
5.KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden
6.Shandong Univ, Hosp 2, 247 Beiyuan Ave, Jinan 250033, Shandong, Peoples R China
7.Uppsala Univ, Dept Chem BMC, Box 576, SE-75123 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 14 期
页码：
收录情况： SCI
摘要： On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.
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