2,4-Diaminopyrido[3,2-d]pyrimidine inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii

Andre Rosowsky, Ronald A. Forsch, Sherry Queener

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Abstract

Six previously unknown 2,4-diamino-6-(anilinomethyl)- and 2,4-diamino-6-[N-methylanilino)methyl]pyrido[3,2-d]pyrimidmes (5-10) were synthesized from 2,4-diamino-6-(bromomethyl)pyrido[3,2-d]pyrimidine hydrobromide (11·HBr) by treatment with the appropriate aniline or N-methylaniline in dimethylformamide at room temperature, with or without NaHCO3 present. Compounds 5-10 were tested as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, and rat liver as a part of a larger effort directed toward the discovery of lipophilic nonclassical antifolates combining high enzyme selectivity and high potency. Of the six analogues tested, the most potent and selective against T. gondii DHFR was 2,4-diamino-6-[(3′,4′,5′-trimethoxy-N-methylanilino)methyl] pyrido[3,2-d]pyrimidine (7), which had an IC50 of 0.0047 μM against this enzyme as compared with 0.026 μM against the rat liver enzyme. The potency of 7 against T. gondii DHFR was similar to that of trimetrexate (TMQ, 1) and piritrexim (PTX, 2) but was >500-fold greater than that of trimethoprim (TMP, 3). However, while 7 was more selective than either TMQ (19×) or PTX (63×) against this enzyme, its selectivity in comparison with TMP was 8-fold lower. 2,4-Diamino-6-[(3′,4′,5′-trimethoxyanilino)methyl]pyrido[3,2- d]pyrimidine (6) was 17-fold less active than 7 and was also less selective. 2,4-Diamino-6-[(3′,4′-dichloro-N-methylanilino)methyl]pyrido[3,2-d] pyrimidine (10) had an IC50 of 0.022 μM against P. carinii DHFR and was comparable in potency to TMQ and PTX. The species selectivity of 10 for P. carinii versus rat liver DHFR was greater than that of either TMQ (21-fold) or PTX (31-fold). On the other hand, even though 10 was slightly more active than TMQ against the P. carinii enzyme, its selectivity was 7-fold lower than that of TMP. Thus, the goal of combining high enzyme binding activity, which is characteristic of the fused-ring compounds TMQ and PTX, with high selectivity for T. gondii and P. carinii DHFR versus rat liver DHFR, which is characteristic of the monocyclic compound TMP, remained unmet in this limited series.

Original languageEnglish
Pages (from-to)2615-2620
Number of pages6
JournalJournal of Medicinal Chemistry
Volume38
Issue number14
StatePublished - 1995

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Folic Acid Antagonists
Pneumocystis carinii
Toxoplasma
Thymidine Monophosphate
Liver
Rats
Enzymes
Inhibitory Concentration 50
Trimetrexate
Dimethylformamide
Trimethoprim
pyrimidine
Temperature
pyrido(3,2-d)pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

2,4-Diaminopyrido[3,2-d]pyrimidine inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii. / Rosowsky, Andre; Forsch, Ronald A.; Queener, Sherry.

In: Journal of Medicinal Chemistry, Vol. 38, No. 14, 1995, p. 2615-2620.

Research output: Contribution to journalArticle

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abstract = "Six previously unknown 2,4-diamino-6-(anilinomethyl)- and 2,4-diamino-6-[N-methylanilino)methyl]pyrido[3,2-d]pyrimidmes (5-10) were synthesized from 2,4-diamino-6-(bromomethyl)pyrido[3,2-d]pyrimidine hydrobromide (11·HBr) by treatment with the appropriate aniline or N-methylaniline in dimethylformamide at room temperature, with or without NaHCO3 present. Compounds 5-10 were tested as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, and rat liver as a part of a larger effort directed toward the discovery of lipophilic nonclassical antifolates combining high enzyme selectivity and high potency. Of the six analogues tested, the most potent and selective against T. gondii DHFR was 2,4-diamino-6-[(3′,4′,5′-trimethoxy-N-methylanilino)methyl] pyrido[3,2-d]pyrimidine (7), which had an IC50 of 0.0047 μM against this enzyme as compared with 0.026 μM against the rat liver enzyme. The potency of 7 against T. gondii DHFR was similar to that of trimetrexate (TMQ, 1) and piritrexim (PTX, 2) but was >500-fold greater than that of trimethoprim (TMP, 3). However, while 7 was more selective than either TMQ (19×) or PTX (63×) against this enzyme, its selectivity in comparison with TMP was 8-fold lower. 2,4-Diamino-6-[(3′,4′,5′-trimethoxyanilino)methyl]pyrido[3,2- d]pyrimidine (6) was 17-fold less active than 7 and was also less selective. 2,4-Diamino-6-[(3′,4′-dichloro-N-methylanilino)methyl]pyrido[3,2-d] pyrimidine (10) had an IC50 of 0.022 μM against P. carinii DHFR and was comparable in potency to TMQ and PTX. The species selectivity of 10 for P. carinii versus rat liver DHFR was greater than that of either TMQ (21-fold) or PTX (31-fold). On the other hand, even though 10 was slightly more active than TMQ against the P. carinii enzyme, its selectivity was 7-fold lower than that of TMP. Thus, the goal of combining high enzyme binding activity, which is characteristic of the fused-ring compounds TMQ and PTX, with high selectivity for T. gondii and P. carinii DHFR versus rat liver DHFR, which is characteristic of the monocyclic compound TMP, remained unmet in this limited series.",
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AB - Six previously unknown 2,4-diamino-6-(anilinomethyl)- and 2,4-diamino-6-[N-methylanilino)methyl]pyrido[3,2-d]pyrimidmes (5-10) were synthesized from 2,4-diamino-6-(bromomethyl)pyrido[3,2-d]pyrimidine hydrobromide (11·HBr) by treatment with the appropriate aniline or N-methylaniline in dimethylformamide at room temperature, with or without NaHCO3 present. Compounds 5-10 were tested as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, and rat liver as a part of a larger effort directed toward the discovery of lipophilic nonclassical antifolates combining high enzyme selectivity and high potency. Of the six analogues tested, the most potent and selective against T. gondii DHFR was 2,4-diamino-6-[(3′,4′,5′-trimethoxy-N-methylanilino)methyl] pyrido[3,2-d]pyrimidine (7), which had an IC50 of 0.0047 μM against this enzyme as compared with 0.026 μM against the rat liver enzyme. The potency of 7 against T. gondii DHFR was similar to that of trimetrexate (TMQ, 1) and piritrexim (PTX, 2) but was >500-fold greater than that of trimethoprim (TMP, 3). However, while 7 was more selective than either TMQ (19×) or PTX (63×) against this enzyme, its selectivity in comparison with TMP was 8-fold lower. 2,4-Diamino-6-[(3′,4′,5′-trimethoxyanilino)methyl]pyrido[3,2- d]pyrimidine (6) was 17-fold less active than 7 and was also less selective. 2,4-Diamino-6-[(3′,4′-dichloro-N-methylanilino)methyl]pyrido[3,2-d] pyrimidine (10) had an IC50 of 0.022 μM against P. carinii DHFR and was comparable in potency to TMQ and PTX. The species selectivity of 10 for P. carinii versus rat liver DHFR was greater than that of either TMQ (21-fold) or PTX (31-fold). On the other hand, even though 10 was slightly more active than TMQ against the P. carinii enzyme, its selectivity was 7-fold lower than that of TMP. Thus, the goal of combining high enzyme binding activity, which is characteristic of the fused-ring compounds TMQ and PTX, with high selectivity for T. gondii and P. carinii DHFR versus rat liver DHFR, which is characteristic of the monocyclic compound TMP, remained unmet in this limited series.

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