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

Aleem Gangjee, Ona Adair, Sherry Queener

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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
Pages (from-to)2929-2935
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume9
Issue number11
DOIs
StatePublished - 2001

Fingerprint

Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Pneumocystis carinii
Pyrimidines
Toxoplasma
Mycobacterium tuberculosis
Liver
Inhibitory Concentration 50
Rats
Growth
pyrido(3,2-d)pyrimidine
In Vitro Techniques
pyrimidine

ASJC Scopus subject areas

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

Cite this

Synthesis of 2,4-Diamino-6-(thioarylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. / Gangjee, Aleem; Adair, Ona; Queener, Sherry.

In: Bioorganic and Medicinal Chemistry, Vol. 9, No. 11, 2001, p. 2929-2935.

Research output: Contribution to journalArticle

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abstract = "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.",
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