ANALOGUES 



more thymine or folic acid. This suggested that these substances 

 displaced thymine from an active enzyme centre, thus supporting the 

 hypothesis first advanced by J. L. Stokes ^ that thymine is the product 

 of an enzyme system of which folic acid is the prosthetic group. 

 Results with other compounds, however, were not consistent with this 

 hypothesis. 5-Bromo uracil, for example, completely inhibited the 

 growth of L. helveticiis in presence of thymine, but not of folic acid, 

 whilst 5-nitrouracil prevented the growth of L. helveticus in presence 

 of folic acid but not of thymine. It would appear therefore that 

 thymine and folic acid act independently of one another and, are not 

 components of one and the same system. 



A series of diaminopteridines with anti-folic acid properties was 

 synthesised by Mallette et al}^ These, with the general formula : 



N ! 



NHo. 



were as follows : — 



(i) 2 : 4-diamino-6 : 7-dimethylpyrimido(4 : 5-5)pyrazine, 



(2) 2 : 4-diamino-6 : 7-dicarboxypyrimido(4 : 5-6)pyrazine, 



(3) 2 : 4-diamino-7-carboxypyrimido(4 : 5-6)pyrazine, 



(4) 2 : 4-diamino-6 : 7-diphenylp5a-imido(4 : 5-6)pyrazine, and 



(5) 2 : 4-diaminopyrimido(4 : 5-6)pyrazine. 



The growth of 5. faecalis, L. helveticus and L. arabinosus (without 

 ;/)-aminobenzoic acid) was inhibited by severial of these compounds. 

 Folic acid overcame this inhibition, the antagonism being competitive.^^ 

 The inhibition indexes of compounds (i) and (4) were 5000 and 10 re- 

 spectively with 5. faecalis and 50,000 and 200,000 with L. helveticus. ^^^ 

 Against E. coli and Staph, aureus, compounds (i) and (4) were the most 

 effective ; sulphathiazole exhibited a synergistic action with both.^^ 

 The carboxypteridines, however, had little effect on E. coli, and only 

 showed a synergistic effect with sulphathiazole when tested on Staph, 

 aureus. Compound (5) had only a slight antibacterial action on either 

 organism, but showed a considerable synergistic effect with sulpha- 

 thiazole. The pteridines and sulphathiazole showed synergism with 

 L. arabinosus also. Folic acid completely overcame the inhibition of 

 growth brought about by low levels of pteridine and sulphonamide but 

 with high levels the antagonism was only partial ; this antagonism was 

 competitive. If, on the other hand, the inhibition of pteridine or sul- 

 phonamide were studied separately, the effect of added folic acid was 

 non-competitive. High levels of folic acid antagonised the growth 



517 



