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Synthesis of 2,6‐diamino‐5‐[(2‐substituted phenylamino)ethyl]pyrimidin‐4(3 h )‐one as inhibitors of folate metabolizing enzymes
Author(s) -
Gangjee Aleem,
Wang Ying,
Queener Sherry F.,
Kisliuk Roy L.
Publication year - 2006
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570430615
Subject(s) - dihydrofolate reductase , chemistry , thymidylate synthase , escherichia coli , guanidine , enzyme , stereochemistry , enzyme inhibitor , toxoplasma gondii , pyrimidine , antifolate , biochemistry , organic chemistry , antimetabolite , medicine , fluorouracil , surgery , chemotherapy , biology , antibody , immunology , gene , toxicity
A series of eleven novel 2,6‐diamino‐5‐[(2‐substituted phenylamino)ethyl]pyrimidin‐4(3 H )‐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(3 H )‐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 IC 50 = 150 μM and 9.1 μM against Escherichia coli and Toxoplasma gondii DHFR, respectively.