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

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.