Discovery of a non-zwitterionic oseltamivir analogue as a potent influenza a neuraminidase inhibitor

Huicong Zhang; Kuanglei Wang; Hongxi Zhu; Xiaodi Zhao; Hongqian Zhao; Zaiqiang Lei; Binfeng Chen; Fei Yang; Kemin Liu; Kun Zhang; Jian Wang; Yongshou Tian

doi:10.1016/j.ejmech.2020.112423

Discovery of a non-zwitterionic oseltamivir analogue as a potent influenza a neuraminidase inhibitor

Eur J Med Chem. 2020 Aug 15:200:112423. doi: 10.1016/j.ejmech.2020.112423. Epub 2020 May 12.

Authors

Huicong Zhang¹, Kuanglei Wang², Hongxi Zhu³, Xiaodi Zhao⁴, Hongqian Zhao³, Zaiqiang Lei³, Binfeng Chen³, Fei Yang³, Kemin Liu³, Kun Zhang⁵, Jian Wang⁶, Yongshou Tian⁷

Affiliations

¹ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
² School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, PR China; School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, PR China.
³ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
⁴ School of Pharmacy, Sungkyunkwan University, Suwon, 16419, South Korea.
⁵ School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, PR China; School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, PR China. Electronic address: kzhang@gdut.edu.cn.
⁶ School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, PR China. Electronic address: wangjian2012@mail.tsinghua.edu.cn.
⁷ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, PR China. Electronic address: tianys@syphu.edu.cn.

PMID: 32512482
DOI: 10.1016/j.ejmech.2020.112423

Abstract

The most of potent neuraminidase inhibitors as zwitterions with poor lipophilicity suffered from the poor oral bioavailability. Herein, we describe a rational journey to discover a non-zwitterionic neuraminidase inhibitor 24a containing urea. It showed potent inhibitions against neuraminidases from group 1(H5N1 and H1N1) and group 2 (H3N2) subtypes and exhibited more strong inhibitory activities against neuraminidases from H274Y mutants than oseltamivir carboxylate. Whether administrated by orally or intravenous injection, the pharmacokinetic profile of compound 24a in SD rats were improved compared to oseltamivir carboxylate.

Keywords: Influenza; Neuraminidase inhibitors; Oral bioavailability; Oseltamivir analogues; Urea.

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Influenza A Virus, H1N1 Subtype / drug effects
Influenza A Virus, H1N1 Subtype / enzymology
Influenza A Virus, H3N2 Subtype / drug effects
Influenza A Virus, H3N2 Subtype / enzymology
Influenza A Virus, H5N1 Subtype / drug effects
Influenza A Virus, H5N1 Subtype / enzymology
Microbial Sensitivity Tests
Molecular Structure
Neuraminidase / antagonists & inhibitors*
Neuraminidase / metabolism
Oseltamivir / chemical synthesis
Oseltamivir / chemistry
Oseltamivir / pharmacology*
Structure-Activity Relationship
Viral Proteins / antagonists & inhibitors*
Viral Proteins / metabolism

Substances

Antiviral Agents
Enzyme Inhibitors
Viral Proteins
Oseltamivir
NA protein, influenza A virus
Neuraminidase