104 AARON BENDICH 



Other pyrimidines active as microbial inhibitors have also been known for many 

 years, and include 5-methylthiouracil,2^'' dithiothymine, and 5-hydroxy-, 5-amino-, 

 5-halo-, and S-nitrouracils.^**"^*" Certain 2,6(4)-diaminopyrimidines containing groups 

 such as benzyl, phenoxy, or phenyl at position 5 are powerful antagonists of folic or 

 folinic acids in a variety of biological systems^^' and inhibit the development of frog 

 gggg 262 (por a discussion of these acids and purine and pyrimidine biosynthesis, see 

 Shive.^^^") The structural resemblance between the antimalarial Paludrine {N'-p- 

 chlorophenyl-A'5-isopropylbiguanide) and certain of these 2,6(4)-diamino-5-aryloxy- 

 pyrimidines led to the suggestion that Paludrine might also possess anti-folic activity 

 and that these pyrimidines might be effective antimalarials. ^^^ These considerations 

 were confirmed upon experimentation, and many active derivatives were prepared. ^*^'^** 

 One of the most eflfective is 2,6(4)-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine 

 (Daraprim),2^^'28^ which is about 1000 times more active than quinine and about 200 

 times more active than Paludrine. It is of interest that the open-chain Paludrine was 

 originally designed from a study of the active structural moiety of active 2-(phenyl- 

 guanidino)pyrimidines.^*' Other examples of pyrimidines used in chemotherapy are 

 the pyrimidine sulfonamides. ^^^ 



Just as in the cases of the pyrimidines cited above, alteration of the 

 structures of naturally occurring purines has yielded compounds of value 

 in biology and medicine. The changes that have furnished important ana- 

 logues to be discussed here have involved substituents at C-2 and C-6 as 

 well as the replacement of carbons 2 and 8 by nitrogen. The 2-amino- 

 substituted adenine, 2 , 6-diaminopurine or DAP^^-'^^'' has been found to 



"4 R. O. Roblin, Jr., Chem. Revs. 38, 255 (1946). 



2** L. D. Wright, Vitamins and Hormones 9, 131 (1951). 



2*6 D. W. Woolley, "A Study of Antimetabolites." Wiley, New York, 1952. 



2" A. Albert, "Selective Toxicity with Special Reference to Chemotherapy." Methuen, 



London, 1951. 

 "8 G. H. Hitchings, G. B. Elion, and E. A. Falco, /. Biol. Chem. 185, 643 (1950). 

 2" G. H. Hitchings, G. B. Elion, E. A. Falco, P. B. Russell, and H. VanderWerfT, Ann. 



N. Y. Acad. Set. 52, 1318 (1950). 



260 G. H. Hitchings, G. B. Elion, E. A. Falco. P. B. Russell, M. B. Sherwood, and H. 

 VanderWerff, /. Biol. Chem. 183, 1 (1950). 



261 G. H. Hitchings, E. A. Falco, H. VanderWerff, P. B. Russell, and G. B. Elion, J. 

 Biol. Chem. 199, 43 (1952). 



262 S. Bieber, R. F. Nigrelli, and G. H. Hitchings, Proc. Soc. Exptl. Biol. Med. 79, 430 

 (1952). 



262a \y Shive Vitamins and Hormones 9, 75 (1951). 



263 E. A. Falco, G. H. Hitchings, P. B. Russell, and H. VanderWerff, Nature 164, 107 

 (1949). 



264 L. G. Goodwin, Nature 164, 1133 (1949). 



266 E. A. Falco, P. B. Russell, and G. H. Hitchings, /. Am. Chem. Soc. 73, 3753 (1951). 



266 p. B. Russell and G. H. Hitchings, /. Am. Chem. Soc. 73, 3763 (1951). 



267 L. H. Schmidt and C. S. Genther, /. Pharmacol. Exptl. Therap. 107, 61 (1953). 



268 H. R. Ing, in "Organic Chemistry, An Advanced Treatise" (Oilman, ed.), Vol. 3, 

 p. 392. Wiley, New York, 1953. 



269 E. H. Northey, "The Sulfonamides and Allied Compounds," p. 31. Reinhold, New 

 York, 1948. 



270 W. Traube, Ber. 37, 4544 (1904). 



