4"-Benzoylureido-TSAO derivatives as potent and selective non-nucleoside HCMV inhibitors. Structure-activity relationship and mechanism of antiviral action.
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.
de Castro
Sonia
S
Instituto de Química Médica (CSIC), Juan de Cierva 3, E-28006 Madrid, Spain.
Peromingo
M Teresa
MT
Naesens
Lieve
L
Andrei
Graciela
G
Snoeck
Robert
R
Balzarini
Jan
J
Velázquez
Sonsoles
S
Camarasa
María-José
MJ
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D014508:Urea; D013936:Thymidine