Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase

Hongqian Zhao; Siyuan Jiang; Zhifan Ye; Hongxi Zhu; Baichun Hu; Peipei Meng; Yanmei Hu; Huicong Zhang; Kuanglei Wang; Jun Wang; Yongshou Tian

doi:10.1016/j.ejmech.2021.113567

Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase

Eur J Med Chem. 2021 Oct 5:221:113567. doi: 10.1016/j.ejmech.2021.113567. Epub 2021 May 23.

Authors

Hongqian Zhao¹, Siyuan Jiang¹, Zhifan Ye¹, Hongxi Zhu¹, Baichun Hu², Peipei Meng¹, Yanmei Hu³, Huicong Zhang⁴, Kuanglei Wang⁵, Jun Wang⁶, Yongshou Tian⁷

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
² School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
³ Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA.
⁴ Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: huicongzhangVIP@163.com.
⁵ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: wangkuangl@163.com.
⁶ Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA. Electronic address: junwang@pharmacy.arizona.edu.
⁷ Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China. Electronic address: tianys@syphu.edu.cn.

PMID: 34082224
DOI: 10.1016/j.ejmech.2021.113567

Abstract

Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound 12 disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound 17a showed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1-H274Y, H1N1-H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stability in vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.

Keywords: 150 cavity; Hydrazide; Influenza A; Neuraminidase inhibitors; Oseltamivir analogues.

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*
Humans
Hydrazines / chemical synthesis
Hydrazines / chemistry
Hydrazines / pharmacology*
Influenza A virus / drug effects*
Influenza A virus / enzymology
Microbial Sensitivity Tests
Molecular Structure
Mutation
Neuraminidase / antagonists & inhibitors*
Neuraminidase / genetics
Neuraminidase / metabolism
Oseltamivir / chemical synthesis
Oseltamivir / chemistry
Oseltamivir / pharmacology*
Structure-Activity Relationship
Viral Proteins / antagonists & inhibitors*
Viral Proteins / genetics
Viral Proteins / metabolism

Substances

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