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 Queener, Malcolm F G Stevens

Research output: Contribution to journalArticle

32 Citations (Scopus)

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

Fingerprint

Folic Acid Antagonists
Pneumocystis carinii
Pyrimethamine
Inhibitory Concentration 50
Derivatives
Liver
Rats
Bearings (structural)
Triazenes
Triazoles
Chemotherapy
Pharmaceutical Preparations
Amines
Pneumocystis Pneumonia
Drug Therapy
Research

ASJC Scopus subject areas

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

Cite this

Structural studies on bioactive compounds. Part 36 : Design, synthesis and biological evaluation of pyrimethamine-based antifolates against Pneumocystis carinii. / Chan, David C M; Laughton, Charles A.; Queener, Sherry; Stevens, Malcolm F G.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 9, 2002, p. 3001-3010.

Research output: Contribution to journalArticle

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