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Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities.

Abstract
With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC(50) values of 0.58 and 2.72 μM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ∼58% protective against AIV infection, which was comparable to zanamivir (∼67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t(1/2)) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.
AuthorsDeju Ye, Woo-Jin Shin, Ning Li, Wei Tang, Enguang Feng, Jian Li, Pei-Lan He, Jian-Ping Zuo, Hanjo Kim, Ky-Youb Nam, Weiliang Zhu, Baik-Lin Seong, Kyoung Tai No, Hualiang Jiang, Hong Liu
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 54 Pg. 764-70 (Aug 2012) ISSN: 1768-3254 [Electronic] France
PMID22795831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Antiviral Agents
  • Enzyme Inhibitors
  • Neuraminidase
  • Zanamivir
Topics
  • Animals
  • Antiviral Agents (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Chemistry Techniques, Synthetic
  • Dogs
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Influenza A Virus, H3N2 Subtype (drug effects, enzymology)
  • Influenza A Virus, H5N1 Subtype (drug effects, enzymology)
  • Madin Darby Canine Kidney Cells
  • Male
  • Neuraminidase (antagonists & inhibitors)
  • Rats
  • Zanamivir (chemical synthesis, chemistry, pharmacokinetics, pharmacology)

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