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

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

  • Eur J Med Chem. 2016 Nov 10:123:397-406. doi: 10.1016/j.ejmech.2016.07.064.
Anindya Das 1,  Avijit K Adak 1,  Kalyankumar Ponnapalli 1,  Chien-Hung Lin 1,  Kai-Cheng Hsu 2,  Jinn-Moon Yang 3,  Tsu-An Hsu 4,  Chun-Cheng Lin 5
Affiliations

Affiliations

  • 1 Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan.
  • 2 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3 Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30050, Taiwan.
  • 4 Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35, Keyan Road, Zhunan 35053, Taiwan.
  • 5 Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan. Electronic address: cclin66@mx.nthu.edu.tw.
PMID: 27487569 DOI: 10.1016/j.ejmech.2016.07.064
Abstract

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.

Keywords

Influenza; Neuraminidase inhibitors; Triazole; Zanamivir.

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