510 THE BIOCHEMISTRY OF B VITAMINS 



stant under the assumed conditions over a range of K a values at a con- 

 stant[H + ] , K = kK f , where k is an integration constant. Substitution of 

 kK f for K in an expression relating the ionization constants of sulfona- 

 mide and dissociation constants of enzyme-drug complexes resulted in an 

 equation relating the activity of the sulfonamides to their ionization 

 constants. However, the evaluation. of k and / is dependent upon experi- 

 mental data. Since the assumptions used in obtaining the equation are 

 the theoretical considerations for which proof is desirable in advance of 

 data, the equation has little to offer other than an empirical expression 

 of the interrelationship of pK a and sulfonamide activity. The final ex- 

 pression is very similar to the one derived by Bell and Roblin. 204 



The assumption that a maximum exists in the activity for variable pK a 

 values is based on the theory that the basic ionic form of the sulfonamide 

 combines with the enzyme which acts as an acid. 206 With increasing 

 ionization constants, the sulfonamides would be expected to increase in 

 activity; however, the increase in acidity of the sulfonamides would re- 

 sult in a decrease in basicity of the ion and decrease the combining power 

 of the ion with the enzyme. Consequently, a maximum in activity may 

 be expected from these theoretical considerations. These considerations 

 do not, however, account for the relatively high activity of certain non- 

 ionizing analogues of p-aminobenzoic acid. 



Effect of Resonance. It has been suggested that the activity of sulfa- 

 nilamides and related compounds is associated with the contribution of 

 the resonating form in which there is a separation of charge, such that a 

 positively charged coplanar amino group is the fundamental factor and 

 the negative character of the S0 2 group is a concomitant factor associated 

 with the resonating form. 207 - 208 The interpretation of some experimental 

 data on physical properties of sulfanilamide supporting this conclusion 209 

 has been questioned. 210 Compounds such as a vinylog of sulfanilamide 211 

 and the p-aminophenyldimethylsulfonium ion, 160 which might be expected 

 to have appreciable activity according to this theory, have been found to 

 be relatively inactive. Other related theories have been proposed. 212 



Miscellaneous Factors Influencing Sulfonamide Activity 



Inhibitory analogues of two metabolites of a biosynthetic sequence 

 usually exert synergistic inhibitory effects. Either ethionine 213 or meth- 

 oxinine, 214 both of which are inhibitory analogues of methionine for 

 Escherichia coli, displays synergistic effects with sulfonamides. Similarly 

 5-amino-7-hydroxy-l-v-triazolo[d]pyrimidine, an inhibitory analogue of 

 guanine, and sulfonamides are synergistic in inhibiting the growth of 

 Staphylococcus aureus and Escherichia coli. 



Many compounds have been reported to act synergistically with sul- 



