The malarial parasite
Plasmodium falciparum depends on the purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) to convert purine bases from the host to nucleotides neededfor DNA and RNA synthesis. An approach to developing antimalarial drugs is to use HGXPRT to convertintroduced purine base analogs to nucleotides that are toxic to the parasite. This strategy requires that thesecompounds be good substrates for the parasite enzyme but poor substrates for the human counterpart, HGPRT.Bases with a chlorine atom in the 6-position or a nitrogen in the 8-position exhibited strong discriminationbetween
P. falciparum HGXPRT and human HGPRT. The
kcat/
Km values for the
Plasmodium enzyme using6-chloroguanine and 8-azaguanine as substrates were 50-80-fold and 336-fold higher than for the humanenzyme, respectively. These and other bases were effective in inhibiting the growth of the parasite in vitro,giving IC
50 values as low as 1
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M.