Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin

Andre Rosowsky, James H. Freisheim, John B. Hynes, Sherry Queener, Marilyn Bartlett, James W. Smith, Herbert Lazarus, Edward J. Modest

Research output: Contribution to journalArticle

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Abstract

A selected number of 1,3-diaminobenzo[f]quinazolines and 1,3-diamino-5,6-dihydrobenzo[f]quinazolines, which may be viewed as tricyclic analogues of the lipid-soluble antifolates pyrimethamine (PM), metoprine (DDMP), and etoprine (DDEP), were tested as inhibitors of purified dihydrofolate reductase (DHFR) from WI-L2 lymphoblasts, and as inhibitors of the growth of Streptococcus faecium ATCC 8043 and L1210 murine leukemia cells in culture. In addition, these tricyclic compounds were tested for antimalarial activity against Plasmodium berghei in mice, and for the ability to inhibit the growth of Pneumocystis carinii trophozoites in WI-38 human lung fibroblast cultures in the presence of leucovorin (LV). The most potent analogues were those with chlorine substitution in the ring distal to the 2,4-diaminopyrimidine moiety. Fully aromatic compounds tended to be more active than those in which the 5,6-bond was reduced, suggesting that planarity favors binding to the DHFR active site and may be favorable for cellular uptake. Several of the 2,4-diaminopyrimidine analogues showed greater potency than PM, DDMP or DDEP, and were more nearly comparable to the bicyclic 2,4-diaminopyrimidine antifolates trimetrexate (TMQ) or piritrexim (BW301U), which are known to be selectively toxic to P. carinii in the presence of LV. Two of the tricyclic compounds, 1,3-diamino-8- chlorobenzo[f]quinazoline and 1,3-diamino-9-chlorobenzo[f]quinazoline, proved to have activity similar to TMQ and BW301U in this system.

Original languageEnglish
Pages (from-to)2677-2684
Number of pages8
JournalBiochemical Pharmacology
Volume38
Issue number16
DOIs
StatePublished - Aug 15 1989

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Quinazolines
Folic Acid Antagonists
Pneumocystis carinii
Leucovorin
Fibroblasts
Pyrimethamine
Lung
Tetrahydrofolate Dehydrogenase
Growth
Trimetrexate
Leukemia L1210
Plasmodium berghei
Enterococcus faecium
Growth Inhibitors
Trophozoites
Aromatic compounds
Poisons
Chlorine
Antimalarials
Cell culture

ASJC Scopus subject areas

  • Pharmacology

Cite this

Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin. / Rosowsky, Andre; Freisheim, James H.; Hynes, John B.; Queener, Sherry; Bartlett, Marilyn; Smith, James W.; Lazarus, Herbert; Modest, Edward J.

In: Biochemical Pharmacology, Vol. 38, No. 16, 15.08.1989, p. 2677-2684.

Research output: Contribution to journalArticle

Rosowsky, Andre ; Freisheim, James H. ; Hynes, John B. ; Queener, Sherry ; Bartlett, Marilyn ; Smith, James W. ; Lazarus, Herbert ; Modest, Edward J. / Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin. In: Biochemical Pharmacology. 1989 ; Vol. 38, No. 16. pp. 2677-2684.
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