168 ANTIBACTERIAL SUBSTANCES FOR TREATMENT OF INFECTIONS 



The necessity for the para position holds also for the antagonistic effect of 

 p-aminobenzoic acid. As Rubbo and Gillespie (1942) showed, o- and m-amino- 

 benzoic acid are poor antagonizers, and very poor essential nutrients for CI. 

 acetobutylicum, as compared with the para form. 



The S of the radicle can be replaced by arsenic, carbon, phosphorus, selenium 

 and tellurium, though not all the compounds so formed are antibacterial, and 

 not all the antibacterial compounds are antagonized by jo-aminobenzoic acid. 

 (Rosenthal et al. 1939, Green and Bielschowsky 1942, Hirsch 1942). The sub- 

 stance 4 : 4'-diaminobenzil, (HaN-CeHi-CO-CO-CeHi-NHj) is sulphur-free, and yet 

 behaves as an active sulphonamide, being antagonized by p-aminobenzoic acid 

 (Kuhn, Moller and Wendt 1943). 



As will be seen from Fig. 27, most of the sulphonamides in general use are 

 derived from sul])honilamide by the introduction of substituents — notably hetero- 

 cyclic radicals — into the amide group. Methylation of the pyrimidine ring of 

 sulphadiazine in the 4- and 4 : 6- position yields sulphamerazine and sulpha - 

 mezathine res])ectively, which have a similarly high degree of activity. The 

 compound Ni-3,4-dimethyl benzoyl sulphanilamide 



H2NCeH,-S02NHCO-C6H3(CH3)2 



is also active, but alteration of the position of the methyl groups in the benzoyl 

 residue completely destroys the activity (Lauger and Martin 1943). 



The bacteriostatic potency of the sulphonamides varies directly with their 

 ability to counteract the antagonistic effect of j9-aminobenzoic acid, i.e. the stronger 

 the drug, the lower its antibacterial index. At about pH 7, that of sulphanilamide 

 lies between 26,000: 1 and 1000: 1. At this pH, however, yj-aminobenzoic acid 

 is almost fully ionized, sulphanilamide very little, and the ratio in terms of anions 

 may be near unity (Fox and Rose 1942). The acid dissociation constants (Ka) 

 of the drugs increase with activity, that of sulphanilamide being 2-2 X 10~^^, 

 sulphapyridine 5-1 X 10~^, and sulphathiazole 6-2 X 10~^, the last approaching 

 most closely to ^-aminobenzoic acid, whose Ka is 1-2 X 10~^ (Schmelkes et al. 

 1942). Albert and Goldacre (1942), on the other hand, suggest that the activity 

 of sulphanilamide and ^-aminobenzoic acid may be a function of their feeble 

 basicity ; both have a Kb of about 10^ ^^. The association between concentration 

 of anions and activity is not, however, constant. Maximum activity may be 

 displayed at a pH at which the solution must contain a mixture of dissociated and 

 undissociated forms (Cowles 1942, Brueckner 1943). It is suggested that both forms 

 are necessary for activity, the non-ionized form alone being capable of penetrating 

 the cell, but the ionized form being an active inhibitor. A similar explanation 

 may apply to Bell and Roblin's (1942) data, which showed that the relation of 

 activity with a high Ka value held good only for a given range of compounds. 

 Above a certain point, activity fell off with increasing Ka. Bell and Roblin, how- 

 ever, postulated that activity depended on the electronegativity of the SOj group, 

 as well as on ionizing capacity. Compounds with the highest Ka are those with 

 substituents on the amide nitrogen possessing a high electron-attracting power 

 and, as a consequence, increasing activity due to increasing acid strength may 

 be counteracted by decrease in the electronegativity of the SOj group. Kumler 

 and Daniels (1943) discuss in some detail the association of activity with the 

 polarity of the molecule, and suggest that it is immaterial whether the sulphona- 



