THE FOLIC ACID GROUP 575 



Inhibitory Analogues of Folic Acid 



The first synthetic inhibitory analogue of folic acid was reported by 

 Martin, Tolman and Moss, 106 who found that a D-methylfolic acid, pre- 

 pared from 2,4,5-triamino-6-hydroxypyrimidine, cc,/?-dibromobutyralde- 

 hyde and N-(p-aminobenzoyl)-D-glutamic acid, competitively prevented 

 the utilization of folic acid by Streptococcus faecalis R. Subsequently, 

 numerous synthetic analogues of folic acid, which prevent the biological 

 functions of the vitamin, have been reported. These inhibitory analogues 

 represent a variety of modifications of the vitamin; some of the more 

 active inhibitors are modifications in which a methyl group has been 

 placed in the pteroyl radical, an amino group has replaced the 4-hydroxyl 

 group of the pteridine ring, a substituent group has been placed at the 

 N 10 -position, or the glutamic acid moiety has been replaced or, in case of 

 modified pteroic acids, omitted. A group of pterins — particularly 2,4- 

 diaminopteridines, with only slight structural resemblance to folic acid 

 in contrast to other folic acid analogues — have been reported to be effec- 

 tive antagonists of folic acid for a number of organisms, including some 

 which synthesize folic acid. 



Substituted Folic, Pteroic and Pteroylaspartic Acids 



Inhibitory analogues of folic acid which can be classed as substituted 

 folic, pteroic, or pteroylaspartic acids are listed with inhibition indices 

 in Table 19. 



x-Methylfolic Acids. The condensation product from a,/3-dibromo- 

 butyraldehyde, 2,4,5-triamino-6-hydroxypyrimidine, and N- (p-amino- 

 benzoyl)-D-giutamic acid inhibits the growth of Streptococcus faecalis 

 R, and the toxicity is competitively prevented by folic acid. The inhibi- 

 tion index is approximately 150. 10G Although no evidence has been pre- 

 sented on the exact structure of this antagonist, it has been designated as 

 7-methylfolic acid. 106 



A similar product was reported which was derived from N-(p-amino- 

 benzoyl)-L-glutamic acid and is considerably more inhibitory for Strep- 

 tococcus faecalis R. 107, 108 The inhibition index for this L-z-methylfolic 

 acid is approximately 20 to 30. 107 The product also inhibits the utiliza- 

 tion of folic acid by Lactobacillus casei at an inhibition index of 100 to 



1000 107, 109 



Either L-z-methylfolic acid or sulfathiazole (1 to 10 mg) prevents the 

 growth of Staphylococcus aureus 209 in a bouillon medium. The toxicity 

 of the methylfolic acid is reported to be prevented by relatively high 

 concentrations (1-10 mg) of p-aminobenzoic acid, folic acid, pteroic acid 

 or sulfathiazole, whereas the toxicity of sulfathiazole is prevented only 

 by p-aminobenzoic acid and pteroic acid. 109b 



Administration of this analogue to a wide variety of organisms results 



