Premium
Analogs of tetrahydrofolic acid. XXVI. synthesis of some 5‐aryl and 5‐aralkyl pyrimidine‐6‐carboxylic acids and their effect on dihydrofolic reductase and thymidylate synthetase
Author(s) -
Baker B. R.,
Jordaan Johannes H.
Publication year - 1965
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.5570020211
Subject(s) - chemistry , pyrimidine , protonation , isopropyl , guanidine , trifluoromethyl , medicinal chemistry , aryl , amide , hydrogen bond , stereochemistry , organic chemistry , molecule , ion , alkyl
2‐Amino‐4‐hydroxy‐5‐(4‐phenylbutyl)pyrimidine‐6‐carboxylic acid (V) was synthesized from isopropyl 2‐ethoxalyl‐6‐phenylhexanoate (XIII) by conversion to acyl guanide (XV) with guanidine followed by anhydrous acid catalyzed ring closure to ethyl 2‐amino‐α‐(4‐phenylbutyl)‐4‐oxo‐2‐imidazoline‐Δ 5,α ‐acetate (XXIII) and base catalyzed rearrangement to V; similarly, p ‐chlorophenylacetonitrile was converted to 5‐( p ‐chlorophenyl)‐2,4‐diaminopyrimidine‐6‐carboxylic acid (VIII). Claisen condensation of isopropyl 6‐phenylhexanoate (XI) or p ‐chlorophenylacetonitrile with ethyl trifluoroacetate followed by condensation with guanidine afforded 2‐amino‐5‐(4‐phenylbutyl)‐6‐(trifluoromethyl)‐4‐pyrimidinol (XXVI) and 5 ‐ ( p ‐chlorophenyl) ‐2,4 ‐diamino‐6‐(trifluoromethyl)pyrimidine (XXXIV). Evaluation of V, VIII, XXVI, and XXXIV as inhibitors of dihydrofolic reductase showed that the 6‐carboxyl, 6‐trifluoromethyl, and 6‐carbethoxy groups greatly reduced the effectiveness as inhibitors of dihydrofolic reductase compared to the corresponding 6‐methyl derivatives. The inhibition data appear to make unlikely the possibility of the pyrimidines binding to the enzyme by four hydrogen bonds as propounded by Zakrzewski (19) or by binding through a charge‐transfer complex, but supports the concept (18) of an anionic‐cationic interaction for the protonated 2,4‐diaminopyrimidines; a weak base ‐weak acid interaction for a non‐protonated pyrimidine that is stronger than a hydrogen bond is also proposed.