Document Report Card

ID: ALA1138206

Journal: J Med Chem

Title: Lead compounds for antimalarial chemotherapy: purine base analogs discriminate between human and P. falciparum 6-oxopurine phosphoribosyltransferases.

Authors: Keough DT, Skinner-Adams T, Jones MK, Ng AL, Brereton IM, Guddat LW, de Jersey J.

Abstract: 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 needed for DNA and RNA synthesis. An approach to developing antimalarial drugs is to use HGXPRT to convert introduced purine base analogs to nucleotides that are toxic to the parasite. This strategy requires that these compounds 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 discrimination between P. falciparum HGXPRT and human HGPRT. The k(cat)/K(m) values for the Plasmodium enzyme using 6-chloroguanine and 8-azaguanine as substrates were 50 - 80-fold and 336-fold higher than for the human enzyme, respectively. These and other bases were effective in inhibiting the growth of the parasite in vitro, giving IC(50) values as low as 1 microM.

CiteXplore: 17149876

DOI: 10.1021/jm061012j