title: Antivirally active ribavirin analogues--4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling.
abstract: BACKGROUND
  Ribavirin is a broad-spectrum antiviral agent that derives some of its activity from inhibition of cellular inosine monophosphate dehydrogenase (IMPDH), resulting in lower guanosine triphosphate (GTP) levels. Here we report the biological activities of three ribavirin analogues.
  
  
  METHODS
  Antiviral activities of test compounds were performed by in vitro cytopathic effect inhibition assays against influenza A (H1N1, H3N2 and H5N1), influenza B, measles, parainfluenza type 3 (PIV-3) and respiratory syncytial viruses. Compounds were modelled into the ribavirin 5'-monophosphate binding site of the crystallographic structure of the human type II IMPDH (hIMPDH2) ternary complex. Effects of compounds on intracellular GTP levels were performed by strong anion exchange HPLC analysis.
  
  
  RESULTS
  Of the three compounds evaluated, the 5-ethynyl nucleoside (ETCAR) exhibited virus-inhibitory activities (at 1.2-20 μM, depending upon the virus) against most of the viruses, except for weak activity against PIV-3 (62 μM). Antiviral activity of ETCAR was similar to ribavirin; however, cytotoxicity of ETCAR was greater than ribavirin. Replacing the 5-ethynyl group with a 5-propynyl or bromo substituent (BrCAR) considerably reduced antiviral activity. Computational studies of ternary complexes of hIMPDH2 enzyme with 5'-monophosphates of the compounds helped rationalize the observed differences in biological activity. All compounds suppressed GTP levels in cells; additionally, BrCAR suppressed adenosine triphosphate and elevated uridine triphosphate levels.
  
  
  CONCLUSIONS
  Three compounds related to ribavirin inhibited IMPDH and had weak to moderate antiviral activity. Cytotoxicity adversely affected the antiviral selectivity of ETCAR. As with ribavirin, reduction in intracellular GTP may play a role in virus inhibition.
authors.affiliation: Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Krajczyk
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulinska
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Kulinski
authors.forename: Brett L
authors.initials: BL
authors.lastname: Hurst
authors.forename: Craig W
authors.initials: CW
authors.lastname: Day
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: Tomasz
authors.initials: T
authors.lastname: Ostrowski
authors.forename: Piotr
authors.initials: P
authors.lastname: Januszczyk
authors.forename: Joanna
authors.initials: J
authors.lastname: Zeidler
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects; D009981:Influenza B virus / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy; D008457:Measles / Q000188:drug therapy; D008459:Measles virus / Q000187:drug effects; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy; D012136:Respiratory Syncytial Viruses / Q000187:drug effects; D010253:Respirovirus Infections / Q000188:drug therapy; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D014230:Triazoles; D012254:Ribavirin