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Irreversible enzyme inhibitors. LXXXV. On the mode of pyrimidine binding of 5‐alkyl and 5‐arylpyrimidines to dihydrofolic reductase
Author(s) -
Baker B. R.,
Lourens Gerhardus J.,
Jordaan Johannes H.
Publication year - 1967
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.5570040107
Subject(s) - chemistry , pyrimidine , stereochemistry , enzyme , hydrogen bond , reductase , covalent bond , ring (chemistry) , alkyl , biochemistry , organic chemistry , molecule
Abstract A series of 5‐isoamyl‐ and 5‐( p ‐chlorophenyl)pyrimidines substituted with amino, alkylamino, mercapto, benzyloxy, hydroxy, or hydrogen at the 2‐ and 4‐positions and with amino or methyl at the 6‐position have been synthesized for evaluation of the mode of pyrimidine binding to dihydrofolic reductase. The studies were performed in order to determine where a bulky group could be placed on the pyrimidine ring that would still allow good binding; such studies are essential to find a suitable position for placement of a covalent forming group for design of active‐site‐directed irreversible inhibitors. Two classes of candidate compounds have emerged for further study as irreversible inhibitors, namely, 2‐amino‐4‐mercapto‐6‐( p ‐bromoacetamidophenylalkyl)‐pyrimidines and 2,4‐diamino‐6‐( p ‐bromoacetamidophenylalkyl)aminopyrimidines having a group such as phenyl, phenylbutyl or isoamyl at the 5‐position that can give strong hydrophobic bonding to the enzyme.