Expeditious Lead Optimization of Isoxazole-Containing Influenza A Virus M2-S31N Inhibitors Using the Suzuki-Miyaura Cross-Coupling Reaction

Fang Li, Yanmei Hu, Yuanxiang Wang, Chunlong Ma, Jun Wang

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The existence of multidrug-resistant influenza viruses, coupled with the continuously antigenic shift and antigenic drift of influenza viruses, necessitates the development of the next-generation of influenza antivirals. As the AM2-S31N mutant persists in more than 95% of current circulating influenza A viruses, targeting the AM2-S31N proton channel appears to be a logical and valid approach to combating drug resistance. Starting from compound 1, an isoxazole compound with potent AM2-S31N channel blockage and antiviral activity, in this study we report an expeditious synthetic strategy that allows us to promptly explore the structure-activity relationships of isoxazole-containing AM2-S31N inhibitors. Propelled by the convenient synthesis, the lead optimization effort yielded a number of potent antivirals with submicromolar efficacy against several human clinical isolates of influenza A viruses, including both oseltamivir-sensitive and -resistant strains.

Original languageEnglish (US)
Pages (from-to)1580-1590
Number of pages11
JournalJournal of Medicinal Chemistry
Volume60
Issue number4
DOIs
StatePublished - Feb 23 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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