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.
Hongqian Zhao  1 ,  Siyuan Jiang  1 ,  Zhifan Ye  1 ,  Hongxi Zhu  1 ,  Baichun Hu  2 ,  Peipei Meng  1 ,  Yanmei Hu  3 ,  Huicong Zhang  4 ,  Kuanglei Wang  5 ,  Jun Wang  6 ,  Yongshou Tian  7
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: [email protected].
  • 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: [email protected].
  • 6. Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA. Electronic address: [email protected].
  • 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: [email protected].
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.
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