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

Expeditious Lead Optimization of Isoxazole-Containing Influenza A Virus M2-S31N Inhibitors Using the Suzuki-Miyaura Cross-Coupling Reaction.
Author Information (click to view)

Li F, Hu Y, Wang Y, Ma C, Wang J,


Li F, Hu Y, Wang Y, Ma C, Wang J, (click to view)

Li F, Hu Y, Wang Y, Ma C, Wang J,

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Journal of medicinal chemistry 2017 02 09() doi 10.1021/acs.jmedchem.6b01852
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.

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