Synthesis of 2,4-Diamino-6-(thioarylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors

Aleem Gangjee, Ona Adair, Sherry F. Queener

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Six 2,4-diaminopyrido[2,3-d]pyrimidines with a 6-merhylthio bridge to an aryl group were synthesize and biologically evaluate as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). The syntheses of analogues 3 8 were achieved by nucleophilic displacemen of 2,4- diamino-6-bromomethylpyrido[2,3-d]pyrimidine 14 with various arylthiols. The α-naphthyl analogue showed the highest selectivity ratios of 3.6 an 8.7 against pcDHFR and tgDHFR, respectively, versus rat liver (rl) DHFR. The b-naphthyl analogue 5 exhibited the highest potency within the series with an IC50 value against pcDHFR and tgDHFR of 0.17 an 0.09 μM, respectively. Analogue 4 was evaluated for in vitro antimycobacterium activity and was shown to inhibit the growth of Mycobacterium tuberculosis H37 Rv cells by 58% a a concentration of 6.25 μg/mL.

Original languageEnglish (US)
Pages (from-to)2929-2935
Number of pages7
JournalBioorganic and Medicinal Chemistry
Issue number11
StatePublished - Oct 9 2001

ASJC Scopus subject areas

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

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