Novel Inhibitors of Pneumocystis carinii and Toxoplasma gondii ...

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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1996, p. 1371–1375 0066-4804/96/$04.0010 Copyright q 1996, American Society for Microbiology

Vol. 40, No. 6

6,7-Disubstituted 2,4-Diaminopteridines: Novel Inhibitors of Pneumocystis carinii and Toxoplasma gondii Dihydrofolate Reductase HELEN C. JACKSON,1* KEITH BIGGADIKE,1 ELAINE MCKILLIGIN,1 OONAGH S. KINSMAN,1 SHERRY F. QUEENER,2 AMANDA LANE,3 AND JUDITH E. SMITH3 Chemotherapy Department and Medicinal Chemistry Department, Glaxo Wellcome Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY,1 and Department of Pure and Applied Biology, University of Leeds, Leeds LS2 9JT,3 United Kingdom, and Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202-51202 Received 21 November 1995/Returned for modification 22 January 1996/Accepted 29 March 1996

Four novel, disubstituted diaminopteridines have been identified which antagonize the uptake of a folate precursor (para-aminobenzoic acid) by rat-derived Pneumocystis carinii maintained in short-term axenic culture at concentrations ranging from 4.5 to 26 mM. The compounds were at least 10 to 100 times more active than trimethoprim in this assay. None of these entities exhibited toxicity to mammalian cell lines at