New 2,4-Diamino-5-(2′,5′-substituted benzyl)pyrimidines as Potential Drugs against Opportunistic Infections of AIDS and Other Immune Disorders. Synthesis and Species-Dependent Antifolate Activity

Andre Rosowsky, Ronald A. Forsch, Carol Hopkins Sibley, Clark B. Inderlied, Sherry Queener

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)-pyrimidine (trimethoprim, TMP) with the potency of 2,4-diamino-5-methyl-6-(2′ ,5′-dimethoxybenzyl)pyrido[2,3-d]pyrimidine (piritrexim, PTX), seven previously undescribed 2,4-diamino-5-[2′-methoxy-5′-(substituted benzyl)]pyrimidines were synthesized in which the substituent at the 5′-position was a carboxyphenyl group linked to the benzyl moiety by a bridge of two or four atoms in length. The new analogues were all obtained from 2,4-diamino-5-(5′-iodo-2′-methoxybenzyl)pyrimidine via a Sonogashira reaction, followed, where appropriate, by catalytic hydrogenation. The new analogues were tested as inhibitors of DHFR from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three life-threatening pathogens often found in AIDS patients and individuals whose immune system is impaired as a result of treatment with immunosuppressive chemotherapy or radiation. The selectivity index (SI) of each compound was obtained by dividing its 50% inhibitory concentration (IC50) against Pc, Tg, or Ma DHFR by its IC50 against rat DHFR. 2,4-Diamino-[2′-methoxy-5′-(3-carboxyphenyl)-ethynylbenzyl] pyrimidine (28), with an IC50 of 23 nM and an SI of 28 in the Pc DHFR assay, had about the same potency as PTX and was 520 times more potent than TMP. As an inhibitor of Tg DHFR, 28 had an IC50 of 5.5 nM (510-fold lower than that of TMP and similar to that of PTX) and an SI value of 120 (2-fold better than TMP and vastly superior to PTX). Against Ma DHFR, 28 had IC50 and SI values of 1.5 nM and 430, respectively, compared with 300 nM and 610 for TMP. Although it had 2.5-fold lower potency than 28 against Ma DHFR (IC50 = 3.7 nM) and was substantially weaker against Pc and Tg DHFR, 2,4-diamino-[2′-methoxy-5′ -(4-carboxyphenyl)ethynylbenzyl]pyrimidine (29), with the carboxy group at the para rather than the meta position, displayed 2200-fold selectivity against the Ma enzyme and was the most selective 2,4-diamino-5-(5′-substituted benzyl)pyrimidine inhibitor of this enzyme we have encountered to date. Additional bioassay data for these compounds are also reported.

Original languageEnglish
Pages (from-to)1475-1486
Number of pages12
JournalJournal of Medicinal Chemistry
Volume47
Issue number6
DOIs
StatePublished - Mar 11 2004

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Folic Acid Antagonists
Pyrimidines
Tetrahydrofolate Dehydrogenase
Immune System Diseases
Opportunistic Infections
Mycobacterium avium
Inhibitory Concentration 50
Trimethoprim
Acquired Immunodeficiency Syndrome
Pneumocystis carinii
Toxoplasma
Pharmaceutical Preparations
Chemotherapy
Hydrogenation
Bioassay
Immune system
Enzyme Inhibitors
Pathogens
Enzymes
Immunosuppressive Agents

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

New 2,4-Diamino-5-(2′,5′-substituted benzyl)pyrimidines as Potential Drugs against Opportunistic Infections of AIDS and Other Immune Disorders. Synthesis and Species-Dependent Antifolate Activity. / Rosowsky, Andre; Forsch, Ronald A.; Sibley, Carol Hopkins; Inderlied, Clark B.; Queener, Sherry.

In: Journal of Medicinal Chemistry, Vol. 47, No. 6, 11.03.2004, p. 1475-1486.

Research output: Contribution to journalArticle

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abstract = "In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)-pyrimidine (trimethoprim, TMP) with the potency of 2,4-diamino-5-methyl-6-(2′ ,5′-dimethoxybenzyl)pyrido[2,3-d]pyrimidine (piritrexim, PTX), seven previously undescribed 2,4-diamino-5-[2′-methoxy-5′-(substituted benzyl)]pyrimidines were synthesized in which the substituent at the 5′-position was a carboxyphenyl group linked to the benzyl moiety by a bridge of two or four atoms in length. The new analogues were all obtained from 2,4-diamino-5-(5′-iodo-2′-methoxybenzyl)pyrimidine via a Sonogashira reaction, followed, where appropriate, by catalytic hydrogenation. The new analogues were tested as inhibitors of DHFR from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three life-threatening pathogens often found in AIDS patients and individuals whose immune system is impaired as a result of treatment with immunosuppressive chemotherapy or radiation. The selectivity index (SI) of each compound was obtained by dividing its 50{\%} inhibitory concentration (IC50) against Pc, Tg, or Ma DHFR by its IC50 against rat DHFR. 2,4-Diamino-[2′-methoxy-5′-(3-carboxyphenyl)-ethynylbenzyl] pyrimidine (28), with an IC50 of 23 nM and an SI of 28 in the Pc DHFR assay, had about the same potency as PTX and was 520 times more potent than TMP. As an inhibitor of Tg DHFR, 28 had an IC50 of 5.5 nM (510-fold lower than that of TMP and similar to that of PTX) and an SI value of 120 (2-fold better than TMP and vastly superior to PTX). Against Ma DHFR, 28 had IC50 and SI values of 1.5 nM and 430, respectively, compared with 300 nM and 610 for TMP. Although it had 2.5-fold lower potency than 28 against Ma DHFR (IC50 = 3.7 nM) and was substantially weaker against Pc and Tg DHFR, 2,4-diamino-[2′-methoxy-5′ -(4-carboxyphenyl)ethynylbenzyl]pyrimidine (29), with the carboxy group at the para rather than the meta position, displayed 2200-fold selectivity against the Ma enzyme and was the most selective 2,4-diamino-5-(5′-substituted benzyl)pyrimidine inhibitor of this enzyme we have encountered to date. Additional bioassay data for these compounds are also reported.",
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