Synthesis of 9-phosphonoalkyl and 9-phosphonoalkoxyalkyl purines: Evaluation of their ability to act as inhibitors of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine–guanine–(xanthine) phosphoribosyltransferases Michal C ˇ esnek a,⇑ , Dana Hocková a , Antonín Holy ´ a , Martin Drac ˇínsky ´ a , Ondr ˇej Baszczyn ˇ ski a , John de Jersey b , Dianne T. Keough b , Luke W. Guddat b a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic b The School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia article info Article history: Received 9 August 2011 Revised 15 November 2011 Accepted 17 November 2011 Available online 1 December 2011 Keywords: Plasmodium falciparum Plasmodium vivax Acyclic nucleoside phosphonates Malaria Hypoxanthine–guanine–xanthine Phosphoribosyltransferase abstract The purine salvage enzyme, hypoxanthine–guanine–(xanthine) phosphoribosyltransferase [HG(X)PRT], catalyses the synthesis of the purine nucleoside monophosphates, IMP, GMP or XMP essential for DNA/RNA production. In protozoan parasites, such as Plasmodium, this is the only route available for their synthesis as they lack the de novo pathway which is present in human cells. Acyclic nucleoside phospho- nates (ANPs), analogs of the purine nucleoside monophosphates, have been found to inhibit Plasmodium falciparum (Pf) HGXPRT and Plasmodium vivax (Pv) HGPRT with K i values as low as 100 nM. They arrest parasitemia in cell based assays with IC 50 values of the order of 1–10 lM. ANPs with phosphonoalkyl and phosphonoalkoxyalkyl moieties linking the purine base and phosphonate group were designed and synthesised to evaluate the influence of this linker on the potency and/or selectivity of the ANPs for the human and malarial enzymes. This data shows that variability in the linker, as well as the posi- tioning of the oxygen in this linker, influences binding. The human enzyme binds the ANPs with K i values of 0.5 lM when the number of atoms in the linker was 5 or 6 atoms. However, the parasite enzymes have little affinity for such long chains unless oxygen is included in the three-position. In comparison, all three enzymes have little affinity for ANPs where the number of atoms linking the base and the phosphonate group is of the order of 2–3 atoms. The chemical nature of the purine base also effects the K i values. This data shows that both the linker and the purine base play an important role in the binding of the ANPs to these three enzymes. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Malaria remains one of the most serious infectious diseases in the world today. Due to increasing resistance to current medications, there is a need to develop new classes of antimalarial drugs. 1 Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the most widespread species that cause malaria in humans. Pf is reputed to be the most lethal but Pv is also responsible for serious illness with recurring bouts of fever. 2 One significant difference in the metabolic pathways between Plasmodium and its human host cell is in the ability to synthesise the purine nucleoside monophosphates essential for the production of DNA/RNA. Mammalian cells are able to produce these metabo- lites either by de novo synthesis or by salvage. In contrast, the malarial parasite possesses only one pathway and this is the salvage of preformed bases transported from its host cell. Hypoxanthine– guanine–xanthine phosphoribosyltransferase (HGXPRT) is the pur- ine salvage enzyme which catalyses the reaction shown in Fig. 1. 3,4 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.11.034 ⇑ Corresponding author. Tel.: +420220183262; fax: +420220183560. E-mail address: cesnekm@uochb.cas.cz (M. C ˇ esnek). HN N N H N O R O O O P P O O O O O O P O O O HO OH Mg 2+ HN N N N O R O O P O O O HO OH PP i R = H, Hypoxanthine NH 2 , Guanine OH, Xanthine Figure 1. Reaction catalyzed by HGXPRT. Bioorganic & Medicinal Chemistry 20 (2012) 1076–1089 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc