Broad-spectrum antiherpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpesvirus polymerase inhibitors.
Through broad screening of the compound library at Pharmacia, a naphthalene carboxamide was identified as a nonnucleoside inhibitor of human cytomegalovirus (HCMV) polymerase. Structure-activity relationship studies demonstrated that a quinoline ring could be substituted for naphthalene, resulting in the discovery of a 4-hydroxyquinoline-3-carboxamide (4-HQC) class of antiviral agents with unique biological properties. In vitro assays with the 4-HQCs have demonstrated potent inhibition of HCMV, herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV) polymerases but no inhibition of human alpha, delta, and gamma polymerases. Antiviral cell culture assays have further confirmed that these compounds are active against HCMV, HSV-1, HSV-2, VZV, and many animal herpesviruses. However, these compounds were not active against several nonherpesviruses representing different DNA and RNA virus families. A strong correlation between the viral DNA polymerase and antiviral activity for this class of compounds supports inhibition of the viral polymerase as the mechanism of antiviral activity. Northern blot analysis of immediate-early and late viral transcripts also pointed to a block in the viral life cycle consistent with inhibition of viral DNA replication. In vitro HCMV polymerase assays indicate that the 4-HQCs are competitive inhibitors of nucleoside binding. However, no cross-resistance could be detected with ganciclovir-resistant HCMV or acyclovir-resistant HSV-1 mutants. The unique, broad-spectrum activities of the 4-HQCs may offer new opportunities for treating many of the diseases caused by herpesviruses.
Oien
Nancee L
NL
Discovery Research, Pharmacia Corp., Kalamazoo, Michigan 49001, USA.
Brideau
Roger J
RJ
Hopkins
Todd A
TA
Wieber
Janet L
JL
Knechtel
Mary L
ML
Shelly
John A
JA
Anstadt
Robert A
RA
Wells
Peter A
PA
Poorman
Roger A
RA
Huang
Audris
A
Vaillancourt
Vallerie A
VA
Clayton
Terrance L
TL
Tucker
John A
JA
Wathen
Michael W
MW
D000577:Amides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D010948:Viral Plaque Assay
D000577:Amides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; D019384:Nucleic Acid Synthesis Inhibitors