title: Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity.
abstract: Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.
authors: School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane 4072, Queensland, Australia.
authors: Dianne T
authors: DT
authors: Keough
authors: Petr
authors: P
authors: Špaček
authors: Dana
authors: D
authors: Hocková
authors: Tomáš
authors: T
authors: Tichý
authors: Silvie
authors: S
authors: Vrbková
authors: Lenka
authors: L
authors: Slavětínská
authors: Zlatko
authors: Z
authors: Janeba
authors: Lieve
authors: L
authors: Naesens
authors: Michael D
authors: MD
authors: Edstein
authors: Marina
authors: M
authors: Chavchich
authors: Tzu-Hsuan
authors: TH
authors: Wang
authors: John
authors: J
authors: de Jersey
authors: Luke W
authors: LW
authors: Guddat
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D007041:Hypoxanthine Phosphoribosyltransferase