Design, synthesis and biological evaluation of 2,4-diamino-6-methyl-5- substitutedpyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors

Aleem Gangjee, Hiteshkumar D. Jain, Sherry F. Queener

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Nine novel nonclassical 2,4-diamino-6-methyl-5-thioarylsubstituted-7H- pyrrolo[2,3-d]pyrimidines 2-10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6-diamino-6-methyl-7H-pyrrolo[2,3-d]-pyrimidine, 14. Compound 14, was in turn obtained by chlorination of 4-position of 2-amino-6-methylpyrrolo[2,3-d] pyrimidin-4(3H)-one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5-position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat-derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1-naphthyl side chain. In this series of compounds electron-withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.

Original languageEnglish (US)
Pages (from-to)589-594
Number of pages6
JournalJournal of Heterocyclic Chemistry
Volume42
Issue number4
DOIs
StatePublished - Jan 1 2005

Fingerprint

Folic Acid Antagonists
Pyrimidines
Tetrahydrofolate Dehydrogenase
Rats
Addition reactions
Electrons
Chlorination
Ammonia
Sulfur
Sulfhydryl Compounds
Iodine
Liver
Antineoplastic Agents
Intermetallics
Ethanol
Atoms
Water
Pyrrolo(2,3-d)pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design, synthesis and biological evaluation of 2,4-diamino-6-methyl-5- substitutedpyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. / Gangjee, Aleem; Jain, Hiteshkumar D.; Queener, Sherry F.

In: Journal of Heterocyclic Chemistry, Vol. 42, No. 4, 01.01.2005, p. 589-594.

Research output: Contribution to journalArticle

@article{2dbd39bd3d6a49c69825dcdacb23c381,
title = "Design, synthesis and biological evaluation of 2,4-diamino-6-methyl-5- substitutedpyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors",
abstract = "Nine novel nonclassical 2,4-diamino-6-methyl-5-thioarylsubstituted-7H- pyrrolo[2,3-d]pyrimidines 2-10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6-diamino-6-methyl-7H-pyrrolo[2,3-d]-pyrimidine, 14. Compound 14, was in turn obtained by chlorination of 4-position of 2-amino-6-methylpyrrolo[2,3-d] pyrimidin-4(3H)-one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5-position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat-derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1-naphthyl side chain. In this series of compounds electron-withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.",
author = "Aleem Gangjee and Jain, {Hiteshkumar D.} and Queener, {Sherry F.}",
year = "2005",
month = "1",
day = "1",
doi = "10.1002/jhet.5570420418",
language = "English (US)",
volume = "42",
pages = "589--594",
journal = "Journal of Heterocyclic Chemistry",
issn = "0022-152X",
publisher = "Heterocorporation",
number = "4",

}

TY - JOUR

T1 - Design, synthesis and biological evaluation of 2,4-diamino-6-methyl-5- substitutedpyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors

AU - Gangjee, Aleem

AU - Jain, Hiteshkumar D.

AU - Queener, Sherry F.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - Nine novel nonclassical 2,4-diamino-6-methyl-5-thioarylsubstituted-7H- pyrrolo[2,3-d]pyrimidines 2-10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6-diamino-6-methyl-7H-pyrrolo[2,3-d]-pyrimidine, 14. Compound 14, was in turn obtained by chlorination of 4-position of 2-amino-6-methylpyrrolo[2,3-d] pyrimidin-4(3H)-one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5-position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat-derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1-naphthyl side chain. In this series of compounds electron-withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.

AB - Nine novel nonclassical 2,4-diamino-6-methyl-5-thioarylsubstituted-7H- pyrrolo[2,3-d]pyrimidines 2-10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6-diamino-6-methyl-7H-pyrrolo[2,3-d]-pyrimidine, 14. Compound 14, was in turn obtained by chlorination of 4-position of 2-amino-6-methylpyrrolo[2,3-d] pyrimidin-4(3H)-one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5-position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat-derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1-naphthyl side chain. In this series of compounds electron-withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.

UR - http://www.scopus.com/inward/record.url?scp=19644399335&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=19644399335&partnerID=8YFLogxK

U2 - 10.1002/jhet.5570420418

DO - 10.1002/jhet.5570420418

M3 - Article

AN - SCOPUS:19644399335

VL - 42

SP - 589

EP - 594

JO - Journal of Heterocyclic Chemistry

JF - Journal of Heterocyclic Chemistry

SN - 0022-152X

IS - 4

ER -