Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase

Malcolm F G Stevens, Keith S. Phillip, Daniel L. Rathbone, Dennis M. O'Shea, Sherry Queener, Carl H. Schwalbe, Peter A. Lambert

Research output: Contribution to journalArticle

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Abstract

Triazenyl-substituted pyrimethamine derivatives 10a-s have been prepared by coupling diazotized 2,4-diamino-5-(3-amino-4-chlorophenyl)-6-ethyl pyrimidine (1c) with a series of secondary amines in aqueous sodium carbonate solution. The triazenes which are stable and poorly soluble as free bases form more soluble, but unstable, salts with alkanesulfonic acids. The lead dimethyltriazene 2,4-diamino-5-[4-chloro-3-(3,3-dimethyltriazen-1-yl)phenyl]- 6-ethylpyrimidine (4a) forms a crystalline ethanesulfonic acid salt (solvated with 2-propanol), which is protonated at the pyrimidine N-1 position as determined by X-ray crystallography. The ability of these new triazenes to inhibit Pneumocystis carinii dihydrofolate reductase in vitro has been compared to that of triazene 4a. The most potent and selective compound, 2,4- diamino-5-[3-[3-[2(acetyloxy)ethyl]-3-benzyltriazen-1-yl]-4-chlorophenyl]-6- ethylpyrimidine (14a), has an IC50 value of 0.17 μM against the microbial enzyme and potentially useful selectivity (rat liver IC50/P. carinii IC50= 114).

Original languageEnglish
Pages (from-to)1886-1893
Number of pages8
JournalJournal of Medicinal Chemistry
Volume40
Issue number12
DOIs
StatePublished - Jun 6 1997

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Triazenes
Pneumocystis carinii
Pyrimethamine
Tetrahydrofolate Dehydrogenase
Inhibitory Concentration 50
Alkanesulfonic Acids
Derivatives
Salts
2-Propanol
X ray crystallography
X Ray Crystallography
Liver
Amines
Rats
Crystalline materials
Enzymes
pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

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Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase. / Stevens, Malcolm F G; Phillip, Keith S.; Rathbone, Daniel L.; O'Shea, Dennis M.; Queener, Sherry; Schwalbe, Carl H.; Lambert, Peter A.

In: Journal of Medicinal Chemistry, Vol. 40, No. 12, 06.06.1997, p. 1886-1893.

Research output: Contribution to journalArticle

Stevens, Malcolm F G ; Phillip, Keith S. ; Rathbone, Daniel L. ; O'Shea, Dennis M. ; Queener, Sherry ; Schwalbe, Carl H. ; Lambert, Peter A. / Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 12. pp. 1886-1893.
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