title: Antiviral agents derived from novel 1-adamantyl singlet nitrenes.
abstract: BACKGROUND
  Amantadine constitutes an interesting, diamond crystal lattice-shaped, antivirally active amine with an inhibitory effect on influenza A viruses causing common 'flu' in humans. Unfortunately, amantadine forfeited most of its therapeutic potential because of resistance development in recent influenza A virus isolates. The antiviral efficacy of amantadine congeners can be chemically modified, resulting in re-constitution, improvement and/or extension of antiviral activities mediated by amino-adamantyls.
  
  
  METHODS
  Newly synthesized compounds were evaluated towards HIV type-1 (HIV-1) replication in primary human lymphocytes. One N-phenacyl amantadine derivative was investigated for inhibiting the in vitro replication of respiratory viruses (influenza A viruses, influenza B virus, human parainfluenza virus type 3 and severe acute respiratory syndrome coronavirus).
  
  
  RESULTS
  Two ketone-stabilized 1-adamantyl singlet nitrenes were discovered serendipitously. To our best knowledge these are the first persistently stable nitrenes to be reported. Their structure was proved by determining the X-ray single crystal structure of one hydrolytic elaboration product. This salt adduct revealed an incommensurately modulated crystal structure, which was solved by extensive computational refinement. We could show that ketone-stabilized 1-adamantyl singlet nitrenes are versatile synthons for the synthesis of antiviral drug candidates. An amantadine-folate conjugate was inhibitory on HIV-1 replication in primary human lymphocytes, and one N-phenacyl amantadine derivative was inhibitory towards low pathogenic avian influenza A virus (H5N1) replication in vitro.
  
  
  CONCLUSIONS
  These results indicate that the aromatic-aliphatic ketone-stabilized 1-adamantyl singlet nitrenes, beyond being of fundamental interest in organic chemistry, represent versatile synthons for the synthesis of new amantadine-related potentially antiviral drugs.
authors.affiliation: Chammünsterstr 47, Munich, Germany. andreas.kesel@gmx.de.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kesel
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Weiss
authors.forename: Andreas
authors.initials: A
authors.lastname: Schönleber
authors.forename: Craig W
authors.initials: CW
authors.lastname: Day
authors.forename: Dale L
authors.initials: DL
authors.lastname: Barnard
authors.forename: Mervi A
authors.initials: MA
authors.lastname: Detorio
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007097:Imines / Q000737:chemistry / Q000494:pharmacology*; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy; D008958:Models, Molecular; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects*; D010253:Respirovirus Infections / Q000188:drug therapy; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy
chemical_list: D000998:Antiviral Agents; D007097:Imines; C017621:phenylnitrene; D000547:Amantadine