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 influen...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2017-02, Vol.60 (4), p.1580-1590
Main Authors: Li, Fang, Hu, Yanmei, Wang, Yuanxiang, Ma, Chunlong, Wang, Jun
Format: Article
Language:English
Subjects:
A549 Cells
Animals
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Dogs
Drug Discovery
Drug Resistance, Multiple
Drug Resistance, Viral
Humans
Influenza A virus - chemistry
Influenza A virus - drug effects
Influenza A virus - genetics
Influenza A Virus, H1N1 Subtype - chemistry
Influenza A Virus, H1N1 Subtype - drug effects
Influenza A Virus, H1N1 Subtype - genetics
Influenza, Human - drug therapy
Isoxazoles - chemistry
Isoxazoles - pharmacology
Madin Darby Canine Kidney Cells
Models, Molecular
Orthomyxoviridae Infections - drug therapy
Point Mutation
Structure-Activity Relationship
Viral Matrix Proteins - antagonists & inhibitors
Viral Matrix Proteins - chemistry
Viral Matrix Proteins - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01852