title: Identification of individual structural fragments of N,N'-(bis-5-nitropyrimidyl)dispirotripiperazine derivatives for cytotoxicity and antiherpetic activity allows the prediction of new highly active compounds.
abstract: OBJECTIVE
  The objectives of this study were (i) to apply computer-based technologies to evaluate the structure of 48 N,N'-(bis-5-nitropyrimidyl)dispirotripiperazines which belong to a new class of highly active antiviral compounds binding to cell surface heparan sulphates, (ii) to understand the chemical- biological interactions governing their activities, and (iii) to design new compounds with strong antiviral activity.
  
  
  METHODS
  The logarithm of 50% cytotoxic concentration (CC(50)) in GMK cells, of 50% inhibitory concentration (IC(50)) against herpes simplex virus type 1, and of selectivity index (SI = CC(50)/IC(50)) was used to develop quantitative structure-activity relationships (QSARs) based on simplex representation of molecular structure. The QSAR model was applied to design new compounds. Two of these compounds were synthesized, physico-chemically characterized and tested for cytotoxicity and antiviral activity.
  
  
  RESULTS
  Statistic characteristics for partial least squares models allow the prediction of CC(50), IC(50) and SI values. The QSAR results demonstrate a high impact of individual structural fragments for antiviral activity. Molecular fragments that promote and interfere with antiviral activity were defined on the basis of the obtained models. Electrostatic factors (38%) and hydrophobicity (34%) were the most important determinants of antiherpetic activity. Using the established method, new potential dispirotripiperazine derivatives were computationally designed. Two of these computationally designed compounds were synthesized. The biological test results confirm the computationally predicted values of these compounds.
  
  
  CONCLUSIONS
  The established QSAR model is suitable for the design of new antiherpetic compounds and prediction of their activity.
authors.affiliation: A.V. Bogatsky Physical-Chemical Institute, Lustdorfskaya doroga 86, Odessa, Ukraine.
authors.forename: A G
authors.initials: AG
authors.lastname: Artemenko
authors.forename: E N
authors.initials: EN
authors.lastname: Muratov
authors.forename: V E
authors.initials: VE
authors.lastname: Kuz'min
authors.forename: N A
authors.initials: NA
authors.lastname: Kovdienko
authors.forename: A I
authors.initials: AI
authors.lastname: Hromov
authors.forename: V A
authors.initials: VA
authors.lastname: Makarov
authors.forename: O B
authors.initials: OB
authors.lastname: Riabova
authors.forename: P
authors.initials: P
authors.lastname: Wutzler
authors.forename: M
authors.initials: M
authors.lastname: Schmidtke
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D019295:Computational Biology; D003588:Cytopathogenic Effect, Viral; D015195:Drug Design; D006497:Heparan Sulfate / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013055:Spectrophotometry, Infrared; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D006497:Heparan Sulfate; D010879:Piperazines; D013141:Spiro Compounds