Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors

Anindya Das, Avijit K. Adak, Kalyankumar Ponnapalli, Chien Hung Lin, Kai Cheng Hsu, Jinn Moon Yang, Tsu An Hsu, Chun Cheng Lin

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The design of potent metabolically stable neuraminidase (NA) inhibitors represents an attractive approach for treating influenza virus infection. In this study, we describe the exploitation of the 150-cavity in the active site of group 1 NA for the design, synthesis, and in vitro evaluation of new triazole-containing N-acyl derivatives related to Zanamivir. Inhibition studies with influenza virus NAs of group 1 (H1N1) and group 2 (H3N2) revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 nM–31 nM) range. Substituents that form stable van der Waals interaction with the 150-cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 6a (H1N1 IC50 = 2.3 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 6a may be attributable to the highly favorable hydrophobic interactions in this region.

Original languageEnglish
Pages (from-to)397-406
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Nov 10 2016



  • Influenza
  • Neuraminidase inhibitors
  • Triazole
  • Zanamivir

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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