D. W. WOOLLEY 



rise to an analogue with no inhibitory powers but rather with weak /'-amino- 

 benzoic acid action. 



Attendant on this increase in activity is an increase in speci- 

 ficity. Benzimidazole is reversed in its action by either adenine or 

 guanine. By contrast, hydroxyaminotriazolopyrimidine competes 

 only with guanine, and aminotriazolopyrimidine interferes only with 

 adenine. However, this increased specificity may not always be 

 desirable, for benzimidazole has pharmacological powers not possessed 

 by the triazolopyrimidines. Furthermore, the effects of the side chains 

 are of interest. In the case of benzimidazole it was thought that the 

 introduction of an amino group in the proper position would make the 

 compound more analogous to adenine, and hence more potent; but 

 the introduction of this side chain did not materially alter the potency 

 of the analogue. In the case of 3,3'-methylenebis-[4-hydroxycou- 

 marin] it would be of interest to learn the effect of the side chains on 

 biological action, that is, whether the introduction of a phytyl group 

 in position 3 (which would make the coumarin more analogous to 

 vitamin K) would increase its potency or modify its action. 



It must not be assumed that it is only necessary to alter the 

 structure of a metabolite indiscriminately in order to achieve an 

 antagonistic agent. Much testing of compounds related structurally 

 to biologically active compounds has indicated that most of these 

 derivatives are inactive under the conditions of test. 



On the other hand, there is no unique manner in which the 

 structure must be altered in order to produce antagonistic agents. 

 For example, 2,4-diamino-7,8-dimethyl-10-ribityl-5,10-dihydrophen- 

 azine, 6,7-dichloro-9-ribitylisoalloxazine, and 5,6-dimethyl-9-ribityl- 

 isoalloxazine, three analogues of riboflavin, all cause riboflavin defi- 

 ciency in various species even though the type of alteration in struc- 

 ture represented by the three compounds is fundamentally differ- 

 ent. Likewise, the structure of />-aminobenzoic acid may be altered 

 by changes either in the nucleus or in the nuclear substituents, with 

 resultant production of substances competing with />-aminobenzoic 

 acid in bacterial growth. It is of interest to note that only a few of these 

 derivatives are active against infections. Similarly, 3-pyTidinesulfonic 

 acid and 3-acetylpyridine represent two inhibitory compounds related 

 to nicotinic acid. Here too, as discussed previously, there are very 



