u-25166 and bropirimine

The modulation of murine host resistance to infection with Listeria monocytogenes by the substituted pyrimidine anti-viral compounds, 2-amino-5-bromo-6-methyl-4-pyrimidinol (ABMP), 2-amino-5-bromo-6-phenyl-4-pyrimidinol (ABPP) and 2-amino-5-iodo-6-phenyl-4-pyrimidinol (AIPP) was investigated. BAF1 mice given three daily injections of ABMP, ABPP (as well as of the interferon-inducer poly I:C) demonstrated enhanced anti-listerial resistance, as measured by a 100-fold increase in the median lethal dose of Listeria compared to vehicle-treated control mice. This enhancement was also detectable as a decrease (up to 100-fold) in the number of viable Listeria recoverable from the livers and spleens of mice during the non-immune phase of natural resistance (24-72 h following infection) to this pathogen. In contrast, AIPP did not enhance anti-listerial resistance. Since each of the effective agents have been shown to induce the production of interferon, the role of interferon in the mechanism of natural resistance to Listeria was evaluated. The serum of untreated B10.A mice infected with Listeria was shown to contain high levels of interferon. Treatment of these mice with a potent anti-mouse interferon antibody preparation completely neutralized circulating interferon activity; however, such treatment had no apparent effect on the growth of Listeria. In addition, mice which received injections of both ABMP and anti-interferon demonstrated a level of resistance identical to that seen in mice given ABMP and normal serum. Based on these results, we propose that although interferon is produced in response to listerial infection, interferon is not a critically important mediator in the mechanism of natural resistance to this pathogen. Furthermore, it appears that the immunomodulating activity of these experimental compounds does not involve interferon.

Topics: Animals; Cytosine; Female; Immunity, Innate; Interferon Inducers; Listeriosis; Male; Mice; Pyrimidines

Topics: Animals; Cytosine; Female; Immunity; Interferon Inducers; Interferons; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Pyrimidines; Pyrimidinones; Virus Diseases

The interferon inducing characteristics of a new series of 6-phenyl pyrimidinol compounds are described and compared against a previously identified pyrimidine, 2-amino-5-bromo-6-methyl-4-pyrimidinol (ABMP). Interestingly, a split in ability to induce interferon but not in vivo antiviral activity was observed in the newest compounds. One representative compound, 2-amino-5-bromo-6-phenyl-4-pyrimidinol (ABPP) induced high levels of serum interferon in mice, cats and cattle in vivo and human lymphoid tissue in vitro and was consistently more active than ABMP. Another representative compound, 2-amino-5-iodo-6-phenyl-4-pyrimidinol (AIPP) was a poor interferon inducer in every system evaluated yet was as active as an in vivo antiviral agent as ABPP or ABMP. The serum interferon response induced by both ABMP and ABPP appeared to originate from an antilymphocyte serum resistant but radiosensitive cell population in the thymus and spleen. These results suggest that the antiviral activity of this group of agents is mediated by both interferon and interferon independent mechanisms.

Topics: Animals; Antiviral Agents; Cats; Cattle; Cells, Cultured; Cytosine; Encephalomyocarditis virus; Female; Fibroblasts; Humans; Hydrocarbons, Halogenated; Interferon Inducers; L Cells; Mice; Mice, Inbred ICR; Pyrimidines; Pyrimidinones; Semliki forest virus; Vesicular stomatitis Indiana virus