6,7-disubstituted 2,4-diaminopteridines

Novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase

Helen C. Jackson, Keith Biggadike, Elaine McKilligin, Oonagh S. Kinsman, Sherry Queener, Amanda Lane, Judith E. Smith

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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 μM. 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 <100 μM. The same structures also caused significant inhibition of Toxoplasma gondii tachyzoite replication within Madin-Darby bovine kidney cells at concentrations ranging from 0.1 to 10 μM. Three of the structures (GR92754, AH10639, and AH2504) were at least an order of magnitude more potent than the standard anti-T. gondii agent, pyrimethamine. All three entities were also significantly more potent and selective than pyrimethamine as inhibitors of T. gondii dihydrofolate reductase (DHFR), with 50% inhibitory concentrations within the range of 0.018 to 0.033 μM. One of these compounds, 6,7-dibutyl-2,4- diaminopteridine (GR92754), was also a potent and selective inhibitor of P. carinii DHFR (50% inhibitory concentration, 0.082 μM). GR92754 is the first DHFR inhibitor described that exhibits greater potency, selectivity, and intracellular activity against both organisms than any of the DHFR agents used clinically, namely, trimethoprim, pyrimethamine, and trimetrexate. This information could provide the starting point for examination of the pharmacokinetic and therapeutic potential of GR92754 and related chemical entities with animal models.

Original languageEnglish
Pages (from-to)1371-1375
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume40
Issue number6
StatePublished - Jun 1996

Fingerprint

Pneumocystis carinii
Pyrimethamine
Tetrahydrofolate Dehydrogenase
Toxoplasma
Trimethoprim
Inhibitory Concentration 50
Trimetrexate
Axenic Culture
4-Aminobenzoic Acid
Folic Acid Antagonists
Folic Acid
Animal Models
Pharmacokinetics
Kidney
Cell Line
2,4-diaminopteridine
Therapeutics

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Jackson, H. C., Biggadike, K., McKilligin, E., Kinsman, O. S., Queener, S., Lane, A., & Smith, J. E. (1996). 6,7-disubstituted 2,4-diaminopteridines: Novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. Antimicrobial Agents and Chemotherapy, 40(6), 1371-1375.

6,7-disubstituted 2,4-diaminopteridines : Novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. / Jackson, Helen C.; Biggadike, Keith; McKilligin, Elaine; Kinsman, Oonagh S.; Queener, Sherry; Lane, Amanda; Smith, Judith E.

In: Antimicrobial Agents and Chemotherapy, Vol. 40, No. 6, 06.1996, p. 1371-1375.

Research output: Contribution to journalArticle

Jackson, Helen C. ; Biggadike, Keith ; McKilligin, Elaine ; Kinsman, Oonagh S. ; Queener, Sherry ; Lane, Amanda ; Smith, Judith E. / 6,7-disubstituted 2,4-diaminopteridines : Novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. In: Antimicrobial Agents and Chemotherapy. 1996 ; Vol. 40, No. 6. pp. 1371-1375.
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