Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities

被引：31

作者：

Ye, Deju ^{[1
]}

Shin, Woo-Jin ^{[2
]}

Li, Ning ^{[1
]}

Tang, Wei ^{[1
]}

Feng, Enguang ^{[1
]}

Li, Jian ^{[1
]}

He, Pei-Lan ^{[1
]}

Zuo, Jian-Ping ^{[1
]}

Kim, Hanjo ^{[3
]}

Nam, Ky-Youb ^{[3
]}

Zhu, Weiliang ^{[1
]}

Seong, Baik-Lin ^{[2
]}

No, Kyoung Tai ^{[2
]}

Jiang, Hualiang ^{[1
]}

Liu, Hong ^{[1
]}

机构：

[1] Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[2] Yonsei Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 120749, South Korea

[3] Bioinformat & Mol Design Res Ctr, Seoul 120749, South Korea

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 54卷

基金：

中国国家自然科学基金;

关键词：

Neuraminidase (NA); Inhibitor; Zanamivir; Avian influenza virus (AIV); H5N1; INFLUENZA-A VIRUS; DRUG DESIGN; 4-GUANIDINO-NEU5AC2EN; DISCOVERY; SIALIDASE;

D O I：

10.1016/j.ejmech.2012.06.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound 026 exerts the most potency, with IC50 values of 0.58 and 2.72 mu M against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts similar to 58% protective against AIV infection, which was comparable to zanamivir (similar to 67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t(1/2)) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents. (C) 2012 Elsevier Masson SAS. All rights reserved.

引用

页码：764 / 770

页数：7

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