39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 4G9 



of amethopterin in such a way as to permit rapid crossing of the "blood- 

 brain barrier," without too great a diminution of the high intrinsic activity 

 of the analog, is a reasonable expectation for the future. 



2. DlAMINOPYRIMIDINES AND DlAMINODIHYDROTRIAZINES 



A sizable group of compounds of the following type structures [(III) and 

 (IV)] has been the subject of much investigation during the past decade. 



NH 2 NH 2 



N C— R 2 N N— R 2 



II I ^R. 



H 2 N— C C— R, H 2 N— C C 



(HI) (IV) 



Although it is not possible entirely to exclude effects of these compounds 

 on other systems, several members of both series which have been investi- 

 gated in considerable detail have been shown to interfere with the forma- 

 tion of coenzymes derived from folic acid. A similar statement can be made 

 concerning the aliphatic antimalarial compound, chloroguanide (Paludrine), 



(p)-Cl— C 6 H— NH— C(=NH)— NH— C(=NH)~ NH— CH(CH 3 ) 2 



since it appears that this drug is conveted metabolically to a diaminodihy- 

 drotriazine (V). 93, 94 



NH 2 NH 2 



The close structural resemblance of the metabolite to the more potent and gener- 

 ally more useful antimalarial, pyrimethamine (VI), a 2,4-diaminopyrimidine, is read- 

 ily apparent. The evidence strongly indicates that each of these antimalarial agents 

 acts primarily by interfering with the formation of FH 4 or a closely related compound 

 by certain plasmodia. 96 " The capacity of pyrimethamine and related compounds 



93 F. Hawking and W. L. M. Perry, Brit. J. Pharmacol. 3, 320 (1948). 



94 H. C. Carrington, A. F. Crowther, D. G. Davey, A. A. Levi, and F. L. Rose, Na- 

 ture 168, 1080 (1951). 



96 G. H. Hitchings, Trans. Roy. Soc. Trop. Med. Hyg. 46, 467 (1952). 

 96 E. J. Modest, G. E. Foley, M. M. Pechet, and S. Farber, J. Am. Chem. Soc. 74, 

 855 (1952). 



