V. SPECIFICITY OF ACTION 153 



creases; the (i.T-diphenyl and Ihe (l.T-plieiuiiitlwo derivatives arc much 

 more active than those coiitaininji; hyihoj^en, methyl, or carboxyl groui)s. 



A synergism between 2,4-diaminopteridine and sulfathiazole has been 

 observed by Daniel and Xorris®^ with E. coli and Staphtjlococcus aureus. For 

 example, 150 7 of 2,4-diamino-(),7-dimethylpteridine per milliliter or 100 

 7 of sulfathiazole is required to i)revent growth of Staphylucoccus aureus, 

 but a combination of 2 7 of each of these gives the same degree of inhibition. 

 With E. coli 100 7 of this same pteritline or 5 7 of sulfathiazole is required 

 to give the same degree of inhibition that can be attained with 10 7 of 

 pteridine plus 1.0 7 of sulfathiazole. This synergistic effect suggests that the 

 two antagonists are acting on two enzyme systems functioning in series. 



The biological effect of a large number of pteridines has been determined 

 for chicks (Daniel et alJ^) and rats (Swendseid et al.^'^). The 2,4-diamino- 

 6,7-diphenylpteridine which is highly inhibitory for S. faecalis has no 

 effect on chick growth and hemoglobin formation.'^*' Swendseid et al.,^^ 

 however, observed that this same compound at a level of 500 mg. per kilo- 

 gram of diet produces leucopenia and a marked granulocytopenia in the rat 

 but has no effect on hemoglobin formation. This leucopenia can be pre- 

 vented by simultaneous feeding of 500 mg. of PGA per kilogram. The 

 corresponding 2,4-diamino-6,7-dimethylpteridine also produces a leu- 

 kemia, but higher le^'els of antagonist are required. The 2-amino-4-hydroxy- 

 G,7-di))henylpteridine is less active than the corresponding 2,4-diamino 

 derivative in producing leucopenia and granulocytopenia in the rat^^ but 

 is more active in depressing growth and hemoglobin formation in the 

 chick.'O 



4. Modification of Pterin Nucleus 



Replacement of the pteridine ring by benzimidazole^" and quinazoline'^^ 

 has yielded growth-promoting compounds rather than inhibitors. The sub- 

 stitution of a sulfonyl group for the carboxyl of p-aminobenzoic acid changes 

 the weak growth-promoting activity of benzimidazole-2-methyl-p-amino- 

 l)enzoylglutaraic acid to a weak antagonist.^" 



Quinoxaline-2-carboxyl3'l-p-aminobenzoylglutamic acid is a weak an- 

 tagonist for S. faecalis.^^ This may, however, be partially due to the fact 

 that there is an amide linkage between the aromatic amine and the quinox- 

 aline group instead of the methylene group present in PGA. The biological 

 activity of these compounds shows that major modifications of the PGA 

 molecule frequently yield growth promoters rather than inhibitors. The 

 formulas of these compounds are shown in Fig. 10. 



" L. J. Daniel and L. C. Norris, J. Biol. L'hem. 170, 747 (1947). 



^» L. J. Daniel, M. L. Scott, L. C. Xorris, and G. F. Heuser, J. Biol. Cfum. 173, 12:^ 



(1948). 

 •' G. J. Martin, J. .Moss, and S. Avakian, J. Biol. ('hem. 167, Hi! (1947). 



