p-AMINOBENZOIC ACID 497 



romyces cerevisiae, tomato roots and Streptobacterium plantarum. The 

 order of effectiveness in some cases depends upon the experimental 

 method, since the dose-response curves for the inhibitory action of the 

 various sulfonamides are not identical under different testing conditions. 

 For example, the growth of the fresh-water diatom, Nitzschia palea var. 

 debilis, is inhibited by sulfanilamide, sulfapyridine and sulfathiazole, 

 with decreasing effectiveness in the order named; however, p-aminoben- 

 zoic acid increases in effectiveness in preventing the toxicities of the 

 sulfonamides in the reverse of the order named. 145-147 A similar situation 

 exists with Saccharomyces cerevisiae 133 and with the nonpigmented alga, 

 chlorella. 143 At low concentrations of p-aminobenzoic acid, sulfapyridine 

 is less effective for Saccharomyces cerevisiae than sulfanilamide, but at 

 higher concentrations of p-aminobenzoic acid such that considerable 

 growth occurs, sulfapyridine is more inhibitory to the organism than is 

 sulfanilamide. 133 Differences in the shape of dose-response curves appear 

 to account for these unusual effects. 



The sulfonamides, sulfones, sulfoxides, etc., which inhibit the utilization 

 of p-aminobenzoic acid usually possess a free amino group in the position 

 para to the sulfur-containing substituent. In a few cases, inhibitory activ- 

 ity has been reported for compounds in which the amino group is replaced 

 by groups, such as nitro, acetylamino, alkylamino, glycosidoamino, etc., 

 which presumably may be converted into a free amino group in the in- 

 hibited biological system. Usually these compounds are less active than 

 the analogous compound with the free amino group. Also substitution of 

 the aromatic ring of this series of sulfur analogues of p-aminobenzoic acid 

 usually results in a decrease or complete loss of inhibitory activity. 



The most effective modifications of sulfanilamide involve N^sub- 

 stituents. In general the inhibitory activity is decreased if the substituent 

 is an alkyl or cycloalkyl group, but is usually increased if the substituent 

 is an aromatic heterocyclic group. Similarly, the most effective sulfones 

 and sulfoxides contain an aromatic group in conjunction with a p-amino- 

 phenyl substituent. 



In contrast to the unusual activity of N-(p-aminobenzoyl)-L-glutamic 

 acid compared with p-aminobenzoic acid in preventing the toxicity of 

 sulfonamides for certain organisms under specific conditions (p. 487), 

 the corresponding sulfonamide, N-sulfanilyl-L-glutamic acid not only 

 does not have increased inhibitory power but is relatively inactive. 67, 1C1 



Reversals with p-Aminobenzoic Acid in Vivo 



Shortly after the preliminary report of Woods and Fildes 1 concerning 

 the ability of p-aminobenzoic acid to prevent the inhibitory action of 

 sulfonamides, Selbie 1G2 found that the therapeutic activity of sulfanila- 



