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.
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.
Fang
F
Li
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.
Yanmei
Y
Hu
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.
Yuanxiang
Y
Wang
BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
Chunlong
C
Ma
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.|BIO5 Institute, The University of Arizona , Tucson, Arizona 85721, United States.
Jun
0000-0002-4845-4621
J
Wang
D000072283:A549 Cells; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery; D018432:Drug Resistance, Multiple; D024882:Drug Resistance, Viral; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D009980:Influenza A virus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D007251:Influenza, Human / Q000188:drug therapy; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D017354:Point Mutation; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000086082:Viroporin Proteins
D000998:Antiviral Agents; D007555:Isoxazoles; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins