Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine analogues of trimetrexate and piritrexim

A. Rosowsky, C. E. Mota, Sherry Queener

Research output: Contribution to journalArticle

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Abstract

2,4-Diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines with di- and trimethoxyaralkyl substitution at the 6-position were synthesized from the N6-unsubstituted compound and appropriate aralkyl bromides in N,N-dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine from 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one was also developed, in which N2 was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4-chloro-phenylphosphorodichloridate and 1,2,4-triazole, ammonolysis to replace the 4-imidazolido group and remove the N2-pivaloyl group, and catalytic hydrogenolysis to remove the 6-benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase from Pneumocystis carinii, and Toxoplasma gondii, and rat liver the most active of the compounds tested was 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μM against the P carinii enzyme, 0.09 μM against the T. gondii enzyme, and 0.35 μM against the rat enzyme. Thus, there was selectivity of binding to T. gondii enzyme, but not P. carinii enzyme, relative to rat enzyme. 2',5'-Dimethoxybenzyl analogues were less active than the corresponding 3',4',5'-trimethoxybenzyl analogues, and compounds with a CH2CH2 or CH2CH2CH2 bridge were less active than those with a CH2 bridge. 2,4-Diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for the P. carinii and T. gondii enzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunistic P. carinii and T. gondii infections in patients with AIDS and other disorders of the immune system.

Original languageEnglish (US)
Pages (from-to)335-340
Number of pages6
JournalJournal of Heterocyclic Chemistry
Volume32
Issue number1
StatePublished - 1995

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Trimetrexate
Folic Acid Antagonists
Enzymes
Rats
Trimethoprim
Sodium Iodide
Sulfamethoxazole
Pyrimethamine
Dimethylformamide
Pyrimidines
Tetrahydrofolate Dehydrogenase
Hydrogenolysis
piritrexim
pyrimidine
Immune system
Enzyme activity
Bromides
Liver
Assays
Substitution reactions

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

@article{6b5189ca1c3446248e2421596b180aec,
title = "Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine analogues of trimetrexate and piritrexim",
abstract = "2,4-Diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines with di- and trimethoxyaralkyl substitution at the 6-position were synthesized from the N6-unsubstituted compound and appropriate aralkyl bromides in N,N-dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine from 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one was also developed, in which N2 was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4-chloro-phenylphosphorodichloridate and 1,2,4-triazole, ammonolysis to replace the 4-imidazolido group and remove the N2-pivaloyl group, and catalytic hydrogenolysis to remove the 6-benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase from Pneumocystis carinii, and Toxoplasma gondii, and rat liver the most active of the compounds tested was 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50{\%} was 0.51 μM against the P carinii enzyme, 0.09 μM against the T. gondii enzyme, and 0.35 μM against the rat enzyme. Thus, there was selectivity of binding to T. gondii enzyme, but not P. carinii enzyme, relative to rat enzyme. 2',5'-Dimethoxybenzyl analogues were less active than the corresponding 3',4',5'-trimethoxybenzyl analogues, and compounds with a CH2CH2 or CH2CH2CH2 bridge were less active than those with a CH2 bridge. 2,4-Diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for the P. carinii and T. gondii enzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunistic P. carinii and T. gondii infections in patients with AIDS and other disorders of the immune system.",
author = "A. Rosowsky and Mota, {C. E.} and Sherry Queener",
year = "1995",
language = "English (US)",
volume = "32",
pages = "335--340",
journal = "Journal of Heterocyclic Chemistry",
issn = "0022-152X",
publisher = "Heterocorporation",
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TY - JOUR

T1 - Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine analogues of trimetrexate and piritrexim

AU - Rosowsky, A.

AU - Mota, C. E.

AU - Queener, Sherry

PY - 1995

Y1 - 1995

N2 - 2,4-Diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines with di- and trimethoxyaralkyl substitution at the 6-position were synthesized from the N6-unsubstituted compound and appropriate aralkyl bromides in N,N-dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine from 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one was also developed, in which N2 was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4-chloro-phenylphosphorodichloridate and 1,2,4-triazole, ammonolysis to replace the 4-imidazolido group and remove the N2-pivaloyl group, and catalytic hydrogenolysis to remove the 6-benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase from Pneumocystis carinii, and Toxoplasma gondii, and rat liver the most active of the compounds tested was 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μM against the P carinii enzyme, 0.09 μM against the T. gondii enzyme, and 0.35 μM against the rat enzyme. Thus, there was selectivity of binding to T. gondii enzyme, but not P. carinii enzyme, relative to rat enzyme. 2',5'-Dimethoxybenzyl analogues were less active than the corresponding 3',4',5'-trimethoxybenzyl analogues, and compounds with a CH2CH2 or CH2CH2CH2 bridge were less active than those with a CH2 bridge. 2,4-Diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for the P. carinii and T. gondii enzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunistic P. carinii and T. gondii infections in patients with AIDS and other disorders of the immune system.

AB - 2,4-Diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines with di- and trimethoxyaralkyl substitution at the 6-position were synthesized from the N6-unsubstituted compound and appropriate aralkyl bromides in N,N-dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine from 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one was also developed, in which N2 was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4-chloro-phenylphosphorodichloridate and 1,2,4-triazole, ammonolysis to replace the 4-imidazolido group and remove the N2-pivaloyl group, and catalytic hydrogenolysis to remove the 6-benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase from Pneumocystis carinii, and Toxoplasma gondii, and rat liver the most active of the compounds tested was 2,4-diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μM against the P carinii enzyme, 0.09 μM against the T. gondii enzyme, and 0.35 μM against the rat enzyme. Thus, there was selectivity of binding to T. gondii enzyme, but not P. carinii enzyme, relative to rat enzyme. 2',5'-Dimethoxybenzyl analogues were less active than the corresponding 3',4',5'-trimethoxybenzyl analogues, and compounds with a CH2CH2 or CH2CH2CH2 bridge were less active than those with a CH2 bridge. 2,4-Diamino-6-(2'-bromo-3',4',5'-trimethoxybenzyl)-5,6,7,8-tetrahydrop yrido[4,3-d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for the P. carinii and T. gondii enzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunistic P. carinii and T. gondii infections in patients with AIDS and other disorders of the immune system.

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