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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
- Source :
- Biochemical pharmacology. 38(16)
- Publication Year :
- 1989
-
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.
- Subjects :
- Leucovorin
In Vitro Techniques
Biochemistry
chemistry.chemical_compound
Antimalarials
Anti-Infective Agents
Dihydrofolate reductase
medicine
Quinazoline
Animals
Humans
Lung
Antibacterial agent
Pharmacology
chemistry.chemical_classification
biology
Bicyclic molecule
Pneumocystis
Growth Inhibitors
Trimetrexate
Pyrimidines
Pneumocystis carinii
chemistry
Antifolate
biology.protein
Folic Acid Antagonists
medicine.drug
Tricyclic
Subjects
Details
- ISSN :
- 00062952
- Volume :
- 38
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- Biochemical pharmacology
- Accession number :
- edsair.doi.dedup.....4e39822a57af8b64a78b7cec27306682