4-Benzyloxy-gamma-sultone derivatives: discovery of a novel family of non-nucleoside inhibitors of human cytomegalovirus and varicella zoster virus.
We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the 4-keto-1,2-oxathiole-2,2-dioxide (beta-keto-gamma-sultone) heterocyclic system. Several 4- and 5-substituted-5H-1,2-oxathiole-2,2-dioxide derivatives were found to have a selective inhibitory activity against human cytomegalovirus (HCMV) and varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. A structure-activity relationship (SAR) study showed that the presence of a benzyl at the 5 position and a benzyloxy substituent at the 4 position are a prerequisite for anti-HCMV and VZV activity. The novel compounds do not show cross-resistance against a wide variety of mutant drug-resistant HCMV strains, pointing to a novel mechanism of antiviral action.
De Castro
Sonia
S
Instituto de Química Médica (CSIC), C/Juan de la Cierva 3, E-28006 Madrid, Spain.
García-Aparicio
Carlos
C
Andrei
Graciela
G
Snoeck
Robert
R
Balzarini
Jan
J
Camarasa
María-José
MJ
Velázquez
Sonsoles
S
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009282:Naphthalenesulfonates / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D009282:Naphthalenesulfonates; C016768:naphthosultone