Lead Compounds for Antimalarial Chemotherapy: Purine Base Analogs Discriminate Between Human and P. Falciparum 6-oxopurine Phosphoribosyltransferases.
From: School of Molecular and Microbial Sciences, The University of Queensland, 4072, Australia.
Journal of medicinal chemistry
- Publish Date: Dec 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 25
- Pages: 7479-86
- Medium: Print
- Language: English
- Citation (JAMA): Keough Dianne T, Skinner-Adams Tina, Jones Malcolm K, et al. Lead Compounds for Antimalarial Chemotherapy: Purine Base Analogs Discriminate Between Human and P. Falciparum 6-oxopurine Phosphoribosyltransferases.. J. Med. Chem. Dec 2006;49:7479-86
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.
Mesh Headings (Keywords): Animals, Antimalarials, Guanine, Humans, Hypoxanthine Phosphoribosyltransferase, Hypoxanthines, Kinetics, Pentosyltransferases, Plasmodium falciparum, Purines, Structure-Activity Relationship
Check for Full Text / PubMed Unique Identifier (PMID): 17149876
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