ABSTRACT
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.
Subject(s)
Amides/pharmacology , Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Herpesviridae/drug effects , Herpesviridae/enzymology , Hydroxyquinolines/pharmacology , Nucleic Acid Synthesis Inhibitors , Binding, Competitive/drug effects , Cell Survival/drug effects , Cells, Cultured , Humans , Kinetics , Structure-Activity Relationship , Substrate Specificity , Viral Plaque AssayABSTRACT
The utility of nitroolefins as "(+)C-C-NH(2)" and "(+)C(C=O)R" synthons is limited by their facile polymerization in the presence of nucleophiles. Although a number of procedures have been developed for the successful alkylation of ketones with nitroolefins, currently available procedures for the corresponding reaction of esters suffer from important limitations such as modest yields, lack of demonstrated generality, inconveniently low reaction temperatures, and/or the use of a large excess of one of the two reactants. In the present work, we examined the efficacy of a series of Lewis acid catalysts for the alkylation of ketene silyl acetals with nitroolefins. Previously reported conditions using diisopropoxytitanium dichloride failed to give satisfactory results with nitroolefins lacking a substituent alpha to the NO(2) group. In contrast, good to excellent results were obtained using sterically congested Lewis acids of the type pioneered by Yamamoto. The successful use of nitroethylene in this reaction represents a significant extension of the utility of this relatively unused "(+)CH(2)CH(2)NH(2)" synthon.