Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the Ki values for human HGPRT and PfHGXPRT was investigated and showed that most of the thia-ANPs distinctively favour PfHGXPRT. For example, the thia-analogue of PEEHx has a Ki value of 0.2 μM for PfHGXPRT, a value 25-fold lower than for the human counterpart. Prodrugs of these compounds have IC50 values in the 4-6 μM range in antimalarial cell-based assays, making them attractive compounds for further development as antimalarial drug leads.

Department of Drug Evaluation Australian Defence Force Malaria and Infectious Disease Institute Enoggera 4051 Australia

Discovery Biology Griffith Institute for Drug Discovery Griffith University Nathan Queensland 4111 Australia

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane 4072 Australia

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane 4072 Australia; Department of Drug Evaluation Australian Defence Force Malaria and Infectious Disease Institute Enoggera 4051 Australia

The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 CZ 16610 Prague 6 Czech Republic

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