4"-Benzoylureido-TSAO Derivatives as Potent and Selective Non-Nucleoside HCMV Inhibitors. Structure-activity Relationship and Mechanism of Antiviral Action

J Med Chem. 2008 Sep 25;51(18):5823-32. doi: 10.1021/jm800050t.

Abstract

Analogues of the 4"-benzoyl-ureido-TSAO derivative (1) modified at different positions have been prepared and evaluated against wild-type strains of HCMV and murine cytomegalovirus (MCMV) in cell culture. In addition, the activity of the most active derivatives against several drug-resistant HCMV mutants has been determined. A stringent structure-antiviral activity relationship was observed for the 4"-benzoylureido- TSAO derivatives for which the concomitant presence of a highly lipophilic substituent at both 2'- and 5'-positions was required to fully preserve the antihuman cytomegalovirus efficacy. Time-of-addition studies and HCMV immediately early and early gene expression studies revealed a target at the time of viral DNA synthesis, although direct inhibition of HCMV-encoded DNA polymerase could not be observed in cell-free assays. Lack of cross-resistance against a broad variety of mutant HCMV strains points to an antiviral target that is different from those drugs that are currently approved for clinical use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Cytomegalovirus / drug effects*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Microbial Sensitivity Tests
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship
  • Thymidine / analogs & derivatives*
  • Thymidine / chemistry
  • Thymidine / pharmacology
  • Urea / analogs & derivatives*
  • Urea / chemistry
  • Urea / pharmacology

Substances

  • Antiviral Agents
  • Urea
  • Thymidine