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As with the polynucleotides, the pyrimidinones exhibited significantactivity against interferon (IFN) sensitive viruses such as Semliki Forest virus invivo. How ever, in addition, they exhibited prophylactic and therapeutic activityupon either local or systemic administration to rodents infected with a variety ofDNA viruses, such as the herpes viruses (HSV-1, HSV-2, CMV andpseudorabies), and when administered intranasally for upper respiratoryinfections, such as infectious bovine rhinortacheites, influenza A and parainfluenza-3.Particularlyinterestion activity was noted with bropirimine onintravaginal administration in protection against HSV-2 intravaginal infection inguinea pigs, an important model for genital herpes in humans. 260 Bropiriminealso exhibited activity when given either intraperitoneally or orally to miceinfected with Listera monocytogenes. The efficacy in this model was notabrogated by the addition of anti-interferon (IFN) antibody. 261Pyrimidines as AntifolatesDuring a preliminary clinical trial designed to establish safety andsuitability for use in the treatment of cancer, Farber found the folic acidderivatives pteroyldiglutamic acid (17) and pteroyltriglutamic acid (18) wereaccelerating the growth of malignant cells in the bone marrow of patients withacute leukaemia. He obtained the newly synthesized antifolate pteroylasparticacid from Subba Row, from which encouraging results were obtained in childrenwith acute leukaemia. Better responses were observed with the aminopterin(19) and methotrexate (20). Injections of methotrexate induced temporaryremissions in 30% of children, but Farber and his colleagues later combined itwith drugs such as cortisone and mercaptopurine to achieve results whichpaved the way towards the currentposition where most children can be curedof the disease if given the appropriate treatment. The precise model of actionof the antifolates became apparent in 1952. This was the inhibitionof dihydrofolate reductase, the enzymes that catalysed the transformation of folic52Pyrimidine…..