title: Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido[2,3-d]pyrimidines as dihydrofolate reductase inhibitors.
abstract: Six 2,4-diaminopyrido[2,3-d]pyrimidines with a 6-methylthio bridge to an aryl group were synthesized and biologically evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). The syntheses of analogues 3-8 were achieved by nucleophilic displacement of 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine 14 with various arylthiols. The alpha-naphthyl analogue 4 showed the highest selectivity ratios of 3.6 and 8.7 against pcDHFR and tgDHFR, respectively, versus rat liver (rl) DHFR. The beta-naphthyl analogue 5 exhibited the highest potency within the series with an IC(50) value against pcDHFR and tgDHFR of 0.17 and 0.09 microM, respectively. Analogue 4 was evaluated for in vitro antimycobacterium activity and was shown to inhibit the growth of Mycobacterium tuberculosis H(37)Rv cells by 58% at a concentration of 6.25 microg/mL.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu
authors.forename: A
authors.initials: A
authors.lastname: Gangjee
authors.forename: O
authors.initials: O
authors.lastname: Adair
authors.forename: S F
authors.initials: SF
authors.lastname: Queener
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D011010:Pneumocystis / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase; D014122:Toxoplasma / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase