DIHYDROFOLATE REDUCTASE FROM TRYPANOSOMA EQUIPERDUM .2. INHIBITION BY 2,4-DIAMINOPYRIMIDINES AND RELATED HETEROCYCLES

A number of 2,4-diaminopyrimidines and related heterocyclic compounds have been evaluated as inhibitors of dihydrofolate reductase obtained from Trypanosoma equiperdum, chicken liver, and rat liver. 2,4-Diaminopvrimidine itself (at 10-4 M) was not effective as an inhibitor of dihydrofolate reduction in all three systems studied but,1-aryl derivatives of 2,4-diaminopyrimidine were good inhibitors (ID30 = 10-8 to 10-6 M) of this enzymatic reaction. 2,4-Diamino-5-benzylpyrimidines and 2,4-diamino-5-aryloxypyrimidines were considerably more effective as inhibitors of the trypanosomal enzyme system than of the mammalian and avian systems. Although 2,4-diamino-6-phenyl-s-tnazine was not active as an inhibitor of the enzymes studied, related 4,6-diamino-1,2-dihydro-s-triazines were potent inhibitors of the reductases. 2,4-Diamino-6,7-diphenylpteridine was found to be approximately tenfold more effective as an inhibitor of the three reductase systems than was 2,4-diamino-6,7-dimethvlpteridine; 2-amino-6,7-diphenylpteridine and 4-amino-6,7-diphenylpteridine were not effective as inhibitors of these enzymes. 2,4,7-Triamino-6-arylpteridines bearing an ortho substituent in the 6-aryl moiety were found to be 10-100-fold more potent as inhibitors of the reductase systems than were the corresponding para-substituted derivatives. The 2-amino-4-hydmxypteridine derivatives biopterin, xanthopterin, and isoxanthopterin were found to be effective neither as substrates nor as inhibitors of the trypanosomal reductase. © 1969, American Chemical Society. All rights reserved.