Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus

被引：41

作者：

Dong, Jianghong ^{[1
]}

Chen, Shengwei ^{[1
]}

Li, Runfeng ^{[2
]}

Cui, Wei ^{[1
]}

Jiang, Haiming ^{[2
]}

Ling, Yixia ^{[1
]}

Yang, Zifeng ^{[2
]}

Hu, Wenhui ^{[1
]}

机构：

[1] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, State Key Lab Resp Dis, 190 Kaiyuan Ave, Guangzhou 510530, Guangdong, Peoples R China

[2] Guangzhou Med Univ, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis, State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 108卷

基金：

美国国家科学基金会;

关键词：

Influenza A virus; M2 ion channel; Pinanamine derivatives; Dual inhibitory activity; M2; ION-CHANNEL; PROTON CHANNEL; ADAMANTANE RESISTANCE; ISOLATED WORLDWIDE; A(H3N2) VIRUSES; H3N2; VIRUSES; ANTIINFLUENZA; EMERGENCE; DESIGN; S31N;

D O I：

10.1016/j.ejmech.2015.12.013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 mu M) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated. (C) 2015 Elsevier Masson SAS. All rights reserved.

引用

页码：605 / 615

页数：11

共 47 条

[1] Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures [J].