Design, synthesis, and in vitro biological evaluation of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents targeting virus nucleoprotein

Huimin Cheng; Junting Wan; Meng-I Lin; Yingxue Liu; Xiaoyun Lu; Jinsong Liu; Yong Xu; Jianxin Chen; Zhengchao Tu; Yih-Shyun E Cheng; Ke Ding

doi:10.1021/jm2013503

Design, synthesis, and in vitro biological evaluation of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents targeting virus nucleoprotein

J Med Chem. 2012 Mar 8;55(5):2144-53. doi: 10.1021/jm2013503. Epub 2012 Feb 27.

Authors

Huimin Cheng¹, Junting Wan, Meng-I Lin, Yingxue Liu, Xiaoyun Lu, Jinsong Liu, Yong Xu, Jianxin Chen, Zhengchao Tu, Yih-Shyun E Cheng, Ke Ding

Affiliation

¹ Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, People's Republic of China.

PMID: 22332894
DOI: 10.1021/jm2013503

Abstract

The influenza virus nucleoprotein (NP) is an emerging target for anti-influenza drug development. Nucleozin (1) and its closely related derivatives had been identified as NP inhibitors displaying anti-influenza activity. Utilizing 1 as a lead molecule, we successfully designed and synthesized a series of 1H-1,2,3-triazole-4-carboxamide derivatives as new anti-influenza A agents. One of the most potent compounds, 3b, inhibited the replication of various H3N2 and H1N1 influenza A virus strains with IC(50) values ranging from 0.5 to 4.6 μM. Compound 3b also strongly inhibited the replication of H5N1 (RG14), amantidine-resistant A/WSN/33 (H1N1), and oseltamivir-resistant A/WSN/1933 (H1N1, 274Y) virus strains with IC(50) values in sub-μM ranges. Further computational studies and mechanism investigation suggested that 3b might directly target influenza virus A nucleoprotein to inhibit its nuclear accumulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amantadine / pharmacology
Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology
Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Cell Line
Dogs
Drug Design
Drug Resistance, Viral
Influenza A Virus, H1N1 Subtype / drug effects
Influenza A Virus, H3N2 Subtype / drug effects
Influenza A Virus, H5N1 Subtype / drug effects
Influenza A virus / drug effects*
Influenza A virus / metabolism
Models, Molecular
Nucleoproteins / metabolism*
Oseltamivir / pharmacology
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Structure-Activity Relationship
Triazoles / chemical synthesis*
Triazoles / chemistry
Triazoles / pharmacology
Viral Core Proteins / metabolism*
Viral Plaque Assay
Virus Replication / drug effects

Substances

(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)(1-(2-methoxyphenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methanone
Amides
Antiviral Agents
Nucleoproteins
Piperazines
Triazoles
Viral Core Proteins
Oseltamivir
Amantadine