Synthesis of 2,6-diamino-5-[(2-substituted phenylamino)ethyl]pyrimidin- 4(3H)-one as inhibitors of folate metabolizing enzymes

Aleem Gangjee, Ying Wang, Sherry F. Queener, Roy L. Kisliuk

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Abstract

A series of eleven novel 2,6-diamino-5-[(2-substituted phenylamino)ethyl] pyrimidin-4(3H)-one derivatives were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The synthesis of analogues 2a-f, 3a and 3e was achieved via an improved method. Commercially available anilines 12a-f were used as starting materials which on reaction with chloroacetaldehyde followed by cyanoacetate and cyclocondensation with guanidine afforded 2,6-diamino-5-[(2-substituted phenylamino)ethyl]pyrimidin-4(3H)-one 2a-f in three steps. The N-methyl analogues 3a-3e were prepared by reductive methylation. These compounds were evaluated against dihydrofolate reductase from Escherichia coli, Toxoplasma gondii, Pneumocystis carinii, human, and rat liver. Few compounds were marginally active against dihydrofolate reductase. The most potent inhibitor, (2c) which has a 1-naphthyl substituent on the side chain, has an IC50 = 150 μM and 9.1 μM against Escherichia coli and Toxoplasma gondii DHFR, respectively.

Original languageEnglish (US)
Pages (from-to)1523-1531
Number of pages9
JournalJournal of Heterocyclic Chemistry
Volume43
Issue number6
DOIs
StatePublished - Nov 1 2006

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ASJC Scopus subject areas

  • Organic Chemistry

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