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Antimicrobial Agents and Chemotherapy, March 2002, p. 724-730, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.724-730.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Broad-Spectrum Antiherpes Activities of 4-Hydroxyquinoline Carboxamides, a Novel Class of Herpesvirus Polymerase Inhibitors

Nancee L. Oien, Roger J. Brideau, Todd A. Hopkins, Janet L. Wieber, Mary L. Knechtel, John A. Shelly, Robert A. Anstadt, Peter A. Wells, Roger A. Poorman, Audris Huang, Vallerie A. Vaillancourt, Terrance L. Clayton, John A. Tucker,{dagger} and Michael W. Wathen*

Discovery Research, Pharmacia Corp., Kalamazoo, Michigan 49001

Received 25 July 2001/ Returned for modification 5 November 2001/ Accepted 17 December 2001

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.

* Corresponding author. Mailing address: Discovery Research, Pharmacia Corp., Kalamazoo, MI 49001. Phone: (616) 833-9362. Fax: (616) 833-0992. E-mail: michael.w.wathen{at}pharmacia.com.

{dagger} Present address: Elan Pharmaceuticals, 800 Gateway Ave., South San Francisco, CA 94080.

Antimicrobial Agents and Chemotherapy, March 2002, p. 724-730, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.724-730.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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