ANALOGUES 



N-(4-[{(2-ainino-4-hydroxy-7-methyl-6-pteridyl) -methyl} -amino] - ben- 

 zoyl) -L-glutamic acid.22 This was prepared by the same reaction as 

 that used to synthesise folic acid, except that 2 : 3-dibromobutyralde- 

 hyde was used in place of 2 : 3-dibromopropionaldehyde. It inhibited 

 competitively the growth-promoting action of folic acid, the ratio of 

 inhibitor to metabolite being 150, by a mechanism different from that 

 involved in sulphonamide inhibition. Thus, the inhibitory action of 

 sulphathiazole towards S. aureus was neutralised by ^^-aminobenzoic 

 acid and by pteroic acid, but not by glutamic acid, ^-aminobenzoyl- 

 glutamic acid or pteroylglutamic acid, whereas the action of 7-methyl- 

 folic acid was neutralised by pteroylglutamic acid, pteroic acid and 

 j5)-aminobenzoic acid but not by ^^-aminobenzoylglutamic acid.^^ This 

 suggests that the synthesis of pteroic acid is the first step in the forma- 

 tion of pteroylglutamic acid, and that methylfolic acid prevents the 

 synthesis of pteroylglutamic acid by interfering with the formation of 

 pteroic acid and its union with glutamic acid. But methylfolic acid 

 also displaced preformed pteroylglutamic acid and, like the sulphon- 

 amides, it interfered with the incorporation of ;/)-aminobenzoic acid 

 into pteroylglutamic acid. The effect of methylfolic acid was counter- 

 acted by sulphathiazole, this being an example of mutual interference 

 by two antagonists. 



The inhibitory action of 7-methylfolic acid was also antagonised 

 by formylfolic acid (page 514) which was actually about thirty times 

 as effective as folic acid, having an antibacterial index of 3000 with 

 5. faecalis R.^^ Synthetic rhizopterine (page 476) was two to three 

 times as effective as folic acid in preventing inhibition. The toxicity 

 of 7-methylfolic acid was increased by heating with formic acid. 

 These results suggest that rhizopterine may be converted directly 

 into formylfolic acid. 



7-Methylfolic acid also antagonised the growth-promoting action 

 of pteroylglutamic acid on L. helveticus and on rats, and again the 

 antagonism was competitive. 2* The effect in rats was to produce 

 symptoms more acute than those produced by feeding a purified 

 diet plus succinylsulphathiazole. 7-Methylfolic acid also produced 

 symptoms of folic acid deficiency in mice, although such symptoms 

 cannot normally be induced merely by feeding a purified diet plus 

 succinylsulphathiazole. It also aggravated a folic acid deficiency in 

 chicks maintained on a purified diet and reduced the response normally 

 elicited in immature chicks by stilboestrol ^s (page 486). 



The antagonist likewise interfered with the metabolism of pteroyl- 

 glutamic acid in the pig, interrupting growth and significantly in- 

 hibiting the formation of erythrocytes and granulocytes.^^ This 

 interference was overcome, even though administration of the 

 antagonist was continued, by feeding normal human gastric juice 



519 



