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Discovery of C-1 modified oseltamivir derivatives as potent influenza neuraminidase inhibitors

文献类型： 外文期刊

作者： Ju, Han 1 ; Zhang, Jian 1 ; Sun, Zhuosen 1 ; Huang, Zheng 1 ; Qi, Wenbao 3 ; Huang, Bing 2 ; Zhan, Peng 1 ; Liu, Xinyong 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.Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China

3.South China Agr Univ, Coll Vet Med, 483 Wushan Rd, Guangzhou 510642, Guangd

关键词： Influenza virus; Neuraminidase inhibitors; 430-Cavity; Oseltamivir derivatives; Embryonated egg model

期刊名称：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY （ 影响因子：6.514； 五年影响因子：6.099 ）

ISSN： 0223-5234

年卷期： 2018 年 146 卷

页码：

收录情况： SCI

摘要： Inspired by our initial discovery about a series of neuraminidase (NA) inhibitors targeting the 150-cavity, in present study, we designed, synthesized, and biologically tested a panel of novel oseltamivir derivatives with C-1 modification, targeting the 430-cavity, an additional binding site which widely and stably existed in both group-1 and group-2 NAs. Some of the synthesized compounds displayed robust anti-influenza potencies against H5N1 and H5N6 viruses. Among them, compound 8b exerted the greatest inhibition, with IC50 values of 0.088 and 0.097 mu M and ECK values of 4.26 and 1.31 mu M against H5N1 and H5N6 strains, respectively, which are similar to those of oseltamivir carboxylate (OSC). And its potency against mutant H5N1-H274Y NA was just 7-fold weaker than OSC. Molecular modeling revealed the elongated group at C-1 position being projected toward the 430-cavity. Notably, although compound 8b was not sensitive toward H5N1 strain relative to OSC in the embryonated egg model, it displayed greater anti-influenza virus effect against H5N6 strain than OSC at the concentration of 10 mmol/L. Overall, this work provided unique insights in the discovery of potent inhibitors against both group-1 and group-2 NAs. (C) 2018 Elsevier Masson SAS. All rights reserved.

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