Biological evidence indicates that the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) is vital for cell proliferation in malarial parasites but nonessential for mammalian cells. 7-Substituted guanines and hypoxanthines in which the 7 substituent bears functional or hydrophobic groups were prepared with the aim of finding a suitably constituted compound whose resemblance to the normal substrate allows it to compete for the reversible purine binding site of HGRPTase while allowing a substituent group of the inhibitor molecule to form a covalent bond or strong hydrophobic bond with appropriate sites on the enzyme. Multistep syntheses that began with hydroxyalkylations and alkylations of guanosine led to four key guanines substituted at the 7 position by the following chains: 2-aminoethyl, 3-amino-2-hydroxypropyl, 3-aminobenzyl, and 4-aminobenzyl. Similarly, 7-(4-aminobenzyl)hypoxanthine was prepared. Reactions at the side-chain amino groups with bromoacetic anhydride (or, alternatively, 4-nitrophenyl bromoacetate) and 3- and 4-(fluorosulfonyl)benzoyl chlorides afforded derivatives bearing functional groups capable of forming covalent bonds with enzymes through displacement reactions. 4-Chlorobenzyl derivatives were similarly prepared as potential inhibitors that might act through hydrophobic bonding. Three 7-substituted guanines whose side chains bear other functions (7-guanine-3-propranesulfonic acid, guanine-7-acetaldehyde, and the ethyl ester of 7-guanine-4-crotonic acid) were prepared as potential inhibitors and for possible use as intermediates. None of these compounds extended the life span of P. berghei infected mice or showed significant in vitro inhibition of HGPRTase from H.Ep.-2 cells.