6-substituted 2,4-diamino-5-methylpyrido[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents.

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Gangjee A, Vasudevan A, Queener SF, Kisliuk RL

6-substituted 2,4-diamino-5-methylpyrido[2,3-d]pyrimidines as inhibitors of dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents.

J Med Chem. 1995 May 12;38(10):1778-85.

PubMed ID
7752201 [ View in PubMed
]
Abstract

The synthesis and biological activity of 15 6-substituted 2,4-diamino-5-methylpyrido[2,3-d]-pyrimidines are reported. These compounds were synthesized in improved yields by modifications of procedures previously reported by us. Specifically, dimethoxyphenyl-substituted compounds with H and CH3 at the N-10 position and trimethoxyphenyl-substituted compounds with N-10 ethyl, isopropyl, and propargyl moieties were synthesized. These compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and rat liver, and selected analogues were evaluated as inhibitors of the growth of T. gondii and tumor cells in culture. All the compounds showed increased selectivity (vs rat liver DHFR) for T. gondii DHFR compared to trimetrexate. In general, for the trimethoxy-substituted analogues, increasing the size of the N-10 substituent from a methyl group to larger groups resulted in a decrease in selectivity and potency for both P. carinii and T. gondii DHFR. For the dimethoxy-substituted analogues, N-10 methylation in general decreased potency but increased selectivity for T. gondii DHFR. In an attempt to improve the cell penetration of these analogues, the N-10 naphthyl-substituted analogues were also synthesized. These analogues displayed excellent cell penetration and inhibition of T. gondii cells in culture. Further, these analogues were potent inhibitors of the growth of tumor cells in the preclinical in-vitro screening program of the National Cancer Institute with IC50s in the nanomolar range.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2,4-Diamino-5-Methyl-6-[(3,4,5-Trimethoxy-N-Methylanilino)Methyl]Pyrido[2,3-D]PyrimidineDihydrofolate reductaseIC 50 (nM)0.85N/AN/ADetails
2,4-Diamino-5-Methyl-6-[(3,4,5-Trimethoxy-N-Methylanilino)Methyl]Pyrido[2,3-D]PyrimidineDihydrofolate reductaseIC 50 (nM)200N/AN/ADetails
2,4-Diamino-5-Methyl-6-[(3,4,5-Trimethoxy-N-Methylanilino)Methyl]Pyrido[2,3-D]PyrimidineDihydrofolate reductaseIC 50 (nM)13.2N/AN/ADetails
PiritreximDihydrofolate reductaseIC 50 (nM)38N/AN/ADetails
PiritreximDihydrofolate reductaseIC 50 (nM)11N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)2700N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)12000N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)103N/AN/ADetails
TrimetrexateDihydrofolate reductaseIC 50 (nM)42N/AN/ADetails
TrimetrexateDihydrofolate reductaseIC 50 (nM)10N/AN/ADetails
TrimetrexateDihydrofolate reductaseIC 50 (nM)27N/AN/ADetails