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 F. Queener, Carl H. Schwalbe, Peter A. Lambert

Research output: Contribution to journalArticle

27 Scopus citations


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


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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