508 THE BIOCHEMISTRY OF B VITAMINS 



of the sulfonamide to compete with the p-aminobenzoate ion for the 

 enzyme. 



The ionic form of a sulfonamide has an electronic charge on the amide 

 nitrogen. Since the S0 2 group is electron-attracting, the charge on the 

 adjacent atom is shared. This results in a more negative S0 2 group in 

 the ionized sulfonamide as compared with the corresponding group in the 

 un-ionized form. Consequently, the ionized form of the sulfonamide 

 would be expected by this theory to be considerably more active than the 

 molecular form. 



Sulfanilamide (pK a 3.7x 10- 11 ) at pH 7 is only slightly ionized. Sub- 

 stitution of an electron-attracting group at the N 1 position allows the 

 hydrogen on this nitrogen to escape as a proton much more easily, since 

 the electron density of the nitrogen atom is decreased by the electron- 

 attracting group. As the electron-attracting power of the N 1 substituent 

 increases, the degree of ionization of the sulfonamide increases. 



However, as the electron-attracting power of the N 1 substituent in- 

 creases, the S0 2 group becomes less negative, since the two groups com- 

 pete for the electrons surrounding the nitrogen. Conversely, as the electron 

 donating power of the N 1 substituent increases, the S0 2 group becomes 

 more negative; however, simultaneously the degree of ionization de- 

 creases. These two opposing effects on activity of the sulfonamide would 

 be expected to result in a maximum activity at a definite pK a value, 

 according to the theory. 



With the assumption that the bacteriostatic activity of ^-substituted 

 sulfonamides is proportional to the potential of the S0 2 group and that 

 the potential of the S0 2 group is influenced by the inductive effect of 

 the N 1 substituent, Bell and Roblin derived equations relating the bio- 

 logical activity of sulfonamide ion with the inductive constant of the 

 N 1 substituent. Thus, 



log (k/xC R ) = a(12.3- / R a)- 1 R a 2 = 4.39 -0.255/ R 



Similarly, the biological activity of the molecular form was related to the 

 inductive constant. Thus, 



\og(k/a-x)C R ) = a(-1.3-I R a)-I R a 2 = -0.464-0.255 I R 



where k is a proportionality constant, determined experimentally to be 

 0.001, x is the fraction of the compound in the ionized state, C R is the 

 minimum molar concentration of the compound required for bacterio- 

 stasis, I B is the inductive constant of the N 1 substituent, and a is the 

 fraction of the inductive effect transmitted across each bond and is taken 

 as 1/2.8, the value of Branch and Calvin for a covalent bond. 

 From the above equations, the logarithm of the ratio of the activity of 



