EFFECTS ON PROTOZOA 747 



a butyric acid group influences favorably the parasiticidal/toxic ratio, as 

 in 3-NH2-4-CH2CH2CH2COOH, inert substituents generally do not mark- 

 edly alter the properties when added to another group, and the addition 

 of an acidic group generally reduces the activity and the ratio. However, 

 when the problem presumably centers around complex mechanisms of 

 membrane penetration, it would be surprising if predictable behavior 

 were observed. 



The problem of why the terminal amide group so favors the parasitici- 

 dal/toxic ratio (or reduces the host toxicity so specifically) cannot at the 

 present time be answered. One can say only that, if it is a question of 

 penetration, the protozoal membranes allow the passage of the amides 

 much more readily than do mammalian tissue cells, in comparison with 

 the unsubstituted phenylarsenoxide. It is certainly not the size of the group 

 alone, since the length of the side chain is of relatively little importance 

 here, nor is it merely the amide group, since many of the substituted amide 

 exhibit the same properties (it appears that the — CONH — or — CON= 

 group is the determinant). Furthermore, the sulfonamides behave very 

 similarly. 



The thioarsenites also present an interesting group. These will be dis- 

 cussed in a later section, but it may be noted now that the formation of a 

 dithioarsenite lowers somewhat both the toxicity and the parasiticidal 

 activity, the former more than the latter, so that the ratio increases. Sum- 

 marizing the ten dicysteinyl derivatives in Table 6-12, one can calculate 

 that the toxicity is reduced 33%, the treponemicidal activity reduced 

 14%, and the ratio increased 38%, although there are exceptions. It is 

 evident that these results cannot be explained by the simple hydrolysis 

 of the dithioarsenites to the corresponding derivatives. Anderson et al. 

 (1949) have shown that two dithioarsenites derived from carbarsone oxide 

 are antiamebic but with reduced toxicity, and similar work has brought 

 about the clinical use of certain dithioarsenites. 



Effective Trypanocidal Doses 



Doses effective in clearing the blood of mice of trypanosomes and lethal 

 doses in mice are shown in Table 6-13. If one may presume the right to 

 average such variant values, one obtains the figures in the accompanying 

 tabulation which give a rough idea of the relationships. These figures show 



Trivalent Pentavalent Ratio As (V)/As (III) 



220 



0.27 



