Inhibition of herpesvirus replication by a series of 4-oxo-dihydroquinolines with viral polymerase activity.
Herpesviruses cause a wide variety of human diseases ranging from cold sores and genital herpes to encephalitis, congenital infections and lymphoproliferative diseases. These opportunistic viruses cause major problems in immunocompromised individuals such as transplant recipients, cancer patients, and HIV-infected persons. The current treatment of these infections is not optimal and there is a need for more active, less toxic compounds that might be used in place of or in addition to current therapies. We have evaluated a new series of 4-oxo-dihydroquinolines, which have a different mechanism of action than nucleosides and have activity against multiple herpesviruses. Of the four new compounds evaluated, two (PHA-529311 and PHA-570886) had greater activity than the parent, PHA-183792, against several herpesviruses and one (PHA-568561) was as effective as the parent. A fourth, PHA-243672, was considerably less effective. They had greater efficacy against cytomegalovirus (CMV) than the other herpesviruses tested and also had activity against acyclovir-resistant herpes simplex virus and varicella-zoster virus isolates and ganciclovir or foscarnet-resistant CMV isolates. These results confirm the broad-spectrum efficacy of these compounds against multiple herpesviruses and suggest that members of this class may have a potential role for treatment of a variety of herpesvirus infections.
Hartline
Caroll B
CB
Department of Pediatrics, The University of Alabama School of Medicine, 128 CHB, 1600 6th Avenue South, Birmingham, AL 35233, USA.
Harden
Emma A
EA
Williams-Aziz
Stephanie L
SL
Kushner
Nicole L
NL
Brideau
Roger J
RJ
Kern
Earl R
ER
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines