Antiherpesvirus activity and mechanism of action of indolo-(2,3-b)quinoxaline and analogs.
The antiherpesvirus activity of 14 derivatives of indoloquinoxaline was tested. The most active was 2,3-dimethyl(dimethylaminoethyl)5H-indolo-(2,3-b)quinoxaline, also called B-220. The antiherpesvirus mechanism of B-220 was sought. The compound inhibited replication of herpes simplex virus type 1, cytomegalovirus, and varicella-zoster virus in tissue culture at concentrations of 1 to 5 microM, depending on the cell type used for assay and the amount of virus. Cellular toxicity was seen at a concentration of 10 to 30 microM, and antiviral activity in the human bladder cancer and human embryonic lung fibroblast cell lines tested was found at concentrations 3 to 15 times lower than the concentrations causing cellular toxicity. Viral DNA synthesis, as well as production of early and late viral proteins, was inhibited at 0.5 to 4.5 microM B-220, but viral DNA polymerases tested in vitro were not inhibited at these concentrations. There was no interaction with the pyrophosphate analog foscarnet, and no reversal of the antiviral activity of B-220 occurred with naturally occurring nucleosides. We conclude that the antiviral effect depends on the multiplicity of infection and may occur at the level of viral DNA synthesis and that no interference occurs with pyrophosphate analogs or nucleosides. The more potent activity against viral DNA than against cellular DNA may be caused by a true selectivity for herpesvirus DNA or by the higher metabolism of viral DNA in infected cells.
Harmenberg
J
J
Department of Virology, National Bacteriological Laboratory, Stockholm, Sweden.
Wahren
B
B
Bergman
J
J
Akerfeldt
S
S
Lundblad
L
L
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000956:Antigens, Viral / Q000032:analysis; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D017245:Foscarnet; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000633:toxicity; D009693:Nucleic Acid Hybridization; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology* / Q000633:toxicity; D018139:Simplexvirus / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000956:Antigens, Viral; D000998:Antiviral Agents; D004279:DNA, Viral; D007211:Indoles; D011810:Quinoxalines; C060183:B 220; C057610:9-(4-hydroxy-2-(hydroxymethyl)butyl)-guanine triphosphate; D017245:Foscarnet; D004259:DNA-Directed DNA Polymerase; D010746:Phosphonoacetic Acid; D000212:Acyclovir