Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium

Ronald A. Forsch, Sherry F. Queener, Andre Rosowsky

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

2,4-Diamino-5-[3′,4′-dimethoxy-5′-(5-carboxy-1-pentynyl)] benzylpyrimidine (6) and 2,4-diamino-5-[3′,4′-dimethoxy-5′-(4- carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5′-iodo-3′,4′-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC50) against rat DHFR by its IC50 against Pc, Tg, or Ma DHFR. The IC 50 of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC50 of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC50 of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization.

Original languageEnglish (US)
Pages (from-to)1811-1815
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number7
DOIs
StatePublished - Apr 2004

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium'. Together they form a unique fingerprint.

  • Cite this