Synthesis of a series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines as 5-daza tetracyclic nonclassical antifolates

I. O. Donkor, R. Devraj, Sherry Queener, L. R. Barrows, A. Gangjee

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

A series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines 1-11 were designed as 5-deaza tetracyclic nonclassical, lipophilic antifolates. The compounds were designed as conformationally semi-rigid and rigid analogs of 2,4-diamino-6-phenyl- 12 and 2,4-diamino-7-phenylpyrido[2,3-d]pyrimidines 13 and 14. The target compounds were synthesized by cyclocondensation of chlorovinyl aldehydes obtained from appropriately substituted 1- or 2-tetralone, with 2,4,6-triaminopyrimidine. Compounds 1-11 were evaluated as inhibitors of P. carinii and T. gondii dihydrofolate reductases. These pathogens cause fatal opportunistic infections in AIDS patients. In addition, the selectivity of these agents was evaluated using rat liver dihydrofolate reductase as the mammalian source. In general the benzo[f]pyrimido[4,5-b]quinolines 1-5 were more potent than the corresponding benzo[h]pyrimido[4,5-b]quinoline analogues 6-11 against P. carinii and rat liver dihydrofolate reductase and were equipotent against T. gondii dihydrofolate reductase. Compounds 6-11 were moderately selective towards T. gondii dihydrofolate reductase with IC50s in the 10-7 M range. In contrast analogues 1-5 lacked selectivity against P. carinii or T. gondii dihydrofolate reductase and were, in general, potent inhibitors of rat liver dihydrofolate reductase with IC50s in the 10-8 M range. Analogues 1 and 4 were evaluated against a series of tumor cell lines in vitro and were found to have moderate antitumor activity (IC50 10-6 M). The structure activity/selectivity relationships suggest that benzo[f]pyrimido analogues 1-5 with the phenyl ring substitution in the 'upper' portion of the tetracyclic ring are better accommodated within the rat liver (mammalian) dihydrofolate reductase and P. carinii dihydrofolate reductase active sites compared to the benzo[h]pyrimido analogues 6-11 which have the phenyl ring substitution in the 'lower' portion of the tetracyclic ring. In contrast P. gondii dihydrofolate reductase does not discriminate between the isomers and binds to both series of compounds with similar affinities.

Original languageEnglish (US)
Pages (from-to)1653-1661
Number of pages9
JournalJournal of Heterocyclic Chemistry
Volume33
Issue number6
StatePublished - 1996

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Quinolines
Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Liver
Rats
Substitution reactions
Tetralones
Pyrimidines
Pathogens
Aldehydes
Isomers
Tumors
Cells

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis of a series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines as 5-daza tetracyclic nonclassical antifolates. / Donkor, I. O.; Devraj, R.; Queener, Sherry; Barrows, L. R.; Gangjee, A.

In: Journal of Heterocyclic Chemistry, Vol. 33, No. 6, 1996, p. 1653-1661.

Research output: Contribution to journalArticle

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abstract = "A series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines 1-11 were designed as 5-deaza tetracyclic nonclassical, lipophilic antifolates. The compounds were designed as conformationally semi-rigid and rigid analogs of 2,4-diamino-6-phenyl- 12 and 2,4-diamino-7-phenylpyrido[2,3-d]pyrimidines 13 and 14. The target compounds were synthesized by cyclocondensation of chlorovinyl aldehydes obtained from appropriately substituted 1- or 2-tetralone, with 2,4,6-triaminopyrimidine. Compounds 1-11 were evaluated as inhibitors of P. carinii and T. gondii dihydrofolate reductases. These pathogens cause fatal opportunistic infections in AIDS patients. In addition, the selectivity of these agents was evaluated using rat liver dihydrofolate reductase as the mammalian source. In general the benzo[f]pyrimido[4,5-b]quinolines 1-5 were more potent than the corresponding benzo[h]pyrimido[4,5-b]quinoline analogues 6-11 against P. carinii and rat liver dihydrofolate reductase and were equipotent against T. gondii dihydrofolate reductase. Compounds 6-11 were moderately selective towards T. gondii dihydrofolate reductase with IC50s in the 10-7 M range. In contrast analogues 1-5 lacked selectivity against P. carinii or T. gondii dihydrofolate reductase and were, in general, potent inhibitors of rat liver dihydrofolate reductase with IC50s in the 10-8 M range. Analogues 1 and 4 were evaluated against a series of tumor cell lines in vitro and were found to have moderate antitumor activity (IC50 10-6 M). The structure activity/selectivity relationships suggest that benzo[f]pyrimido analogues 1-5 with the phenyl ring substitution in the 'upper' portion of the tetracyclic ring are better accommodated within the rat liver (mammalian) dihydrofolate reductase and P. carinii dihydrofolate reductase active sites compared to the benzo[h]pyrimido analogues 6-11 which have the phenyl ring substitution in the 'lower' portion of the tetracyclic ring. In contrast P. gondii dihydrofolate reductase does not discriminate between the isomers and binds to both series of compounds with similar affinities.",
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