Structural studies on bioactive compounds. Part 36: Design, synthesis and biological evaluation of pyrimethamine-based antifolates against Pneumocystis carinii

David C.M. Chan, Charles A. Laughton, Sherry F. Queener, Malcolm F.G. Stevens

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

As part of a research effort to improve the quality of current chemotherapy of Pneumocystis carinii pneumonia, we report a structure-based design project to optimise activity, species selectivity and pharmaceutical properties of the triazenyl-pyrimethamine TAB (4) (IC50=0.17 μM; rat liver DHFR IC50/P. carinii DHFR IC50=114). This has led us to design, synthesise and evaluate four new series of pyrimethamine derivatives bearing triazole, triazolium, triazinium and amino moieties at the 3′-position of the p-chlorophenyl ring. Such stabilised `triazene' derivatives address the potentially compromised pharmaceutical profile of TAB and the 3′-amine substituted agents afford conformationally flexible substitutes. The benzylamino-pyrimethamine derivative (24a) (IC50=0.12 μM, rat liver DHFR IC50/P. carinii DHFR IC50: 5.26) was the most potent and the only P. carinii-selective antifolate of the new series.

Original languageEnglish (US)
Pages (from-to)3001-3010
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume10
Issue number9
DOIs
StatePublished - Jul 23 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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