456 



CHEMICAL AGENTS 



Two conclusions flow from this analysis. First, inhibition of the 

 sensitive cell element must be effected by both neutral molecules and 

 ions, although they need not be equally effective. A chemical model 

 for this behavior is analyzed by Briggs (45). Second, the pH at the 

 site of action must be affected by changes in the external pH, in order 

 for the equieffective concentration of the penetrating species to decline 

 as found (these are long-time experiments in which we can assume equi- 

 librium conditions). As mentioned in Chapter 1, the effect of external 

 pH upon cytoplasmic pH is not known with any certainty or precision. 



The significance of pK a can now be assessed (Figure 7). The rise in 

 required concentration for an equal effect begins at about pK a ; at 

 lower pH (higher for a base) there is much less effect of acidity (383). 

 It follows that in theoretical or comparative studies on weak acids or 

 weak bases the effect of ionization can be minimized by assaying activity 

 at a pH at least two units below pK a (for an acid) or above pK a (for a 

 base). There are exceptions to this rule, the sulfonamide antibacterials 

 being the outstanding and best-known example (6, 382). 



The acridine antibacterials exemplify a rather different relation of 

 toxicity to dissociation and pH (4, 6), one which has so far not come 

 to light among organic fungitoxic materials. In this series only the 

 cation is biologically effective. This fact, and observations on the 



Figure 6. The effect of pH on 

 the concentration of 2,4-dinitro- 

 phenol (pK a — 4.0) required to 

 effect a 50 per cent reduction in 

 the growth rate on agar of 

 Trichoderma viride. Curve 1, 

 total concentration; curve 2, 

 concentration of undissociated 

 molecules. Redrawn from 



Simon and Blackman (383), by 

 permission of the Cambridge 

 University Press. 



