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Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors.

Abstract
The adamantanes are a class of anti-influenza drugs that inhibit the M2 ion channel of the influenza A virus. However recently, the clinical effectiveness of these drugs has been called into question due to the emergence of adamantane-insensitive A/M2 mutants. Although we previously reported (1R,2R,3R,5S)-3-pinanamine 3 as a novel inhibitor of the wild type influenza A virus M2 protein (WT A/M2), limited inhibition was found for adamantane-resistant M2 mutants. In this study, we explored whether newly synthesized pinanamine derivatives were capable of inhibiting WT A/M2 and selected adamantane-resistant M2 mutants. Several imidazole and guanazole derivatives of pinanamine were found to inhibit WT A/M2 to a comparable degree as amantadine and one of these compounds 12 exhibits weak inhibition of A/M2-S31N mutant and it is marginally more effective in inhibiting S31NM2 than amantadine. This study provides a new insight into the structural nature of drugs required to inhibit WT A/M2 and its mutants.
AuthorsXin Zhao, Yanling Jie, Matthew R Rosenberg, Junting Wan, Shaogao Zeng, Wei Cui, Yiping Xiao, Zhiyuan Li, Zhengchao Tu, Marco G Casarotto, Wenhui Hu
JournalAntiviral research (Antiviral Res) Vol. 96 Issue 2 Pg. 91-9 (Nov 2012) ISSN: 1872-9096 [Electronic] Netherlands
PMID22982118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • Antiviral Agents
  • Ion Channels
  • M2 protein, Influenza A virus
  • Viral Matrix Proteins
Topics
  • Animals
  • Antiviral Agents (chemical synthesis, chemistry, isolation & purification, pharmacology)
  • Cell Line
  • Humans
  • Influenza A virus (drug effects)
  • Ion Channels (antagonists & inhibitors)
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Viral Matrix Proteins (antagonists & inhibitors)
  • Viral Plaque Assay

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