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Irreversible enzyme inhibitors. LXXXIX. candidate active‐site‐directed irreversible inhibitors of dihydrofolic reductase. X. derivatives of 2‐amino‐5‐benzamidopropyl‐4‐pyrimidinol
Author(s) -
Baker B. R.,
Coward James K.
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.5570040205
Subject(s) - chemistry , active site , phenacyl bromide , enzyme , bromide , stereochemistry , phenacyl , reductase , halogen , amino acid , biochemistry , medicinal chemistry , organic chemistry , alkyl
Since 2‐amino‐5‐benzamidopropyl‐6‐methyl‐4‐pyrimidinol (VII) was a reasonably good reversible inhibitor of dihydrofolic reductase, the benzamido group was substituted with p ‐bromomethyl (XVIIa), m ‐bromomethyl (XVIIIa), and p ‐bromoacetyl (XIXa) groups; these compounds, and the corresponding 6‐phenylpyrimidines, were synthesized from the proper 2‐amino‐5‐aminopropyl‐4‐pyrimidinol (V) by devising methods that were compatible with the high reactivity of the halogen. Compounds XVII‐XIX showed in‐activation of dihydrofolic reductase; the fact that p ‐nitrobenzyl bromide inactivated the enzyme as rapidly as XVII and XVIII and phenacyl bromide inactivated the enzyme as rapidly as XIX indicated that these inactivations proceeded by a random bimolecular mechanism and not the desired active‐site‐directed mechanism.