Lead Compounds for Antimalarial Chemotherapy:  Purine Base Analogs Discriminate between Human and P. Falciparum 6-Oxopurine Phosphoribosyltransferases

• Published in: Journal of medicinal chemistry 2006-12, Vol.49 (25), p.7479-7486
• Main Authors: Keough, Dianne T, Skinner-Adams, Tina, Jones, Malcolm K, Ng, Ai-Lin, Brereton, Ian M, Guddat, Luke W, de Jersey, John
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Guanine - analogs & derivatives; Guanine - chemistry; Guanine - pharmacology; Humans; Hypoxanthine Phosphoribosyltransferase - antagonists & inhibitors; Hypoxanthine Phosphoribosyltransferase - chemistry; Hypoxanthines - chemistry; Hypoxanthines - pharmacology; Kinetics; Medical sciences; Pentosyltransferases - antagonists & inhibitors; Pentosyltransferases - chemistry; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Purines - chemistry; Purines - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061012j

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 IC50 values as low as 1 μM.