title: Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6-Oxopurine Phosphoribosyltransferases.
abstract: Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6 (Czech Republic).
authors.forename: Martin M
authors.initials: MM
authors.lastname: Kaiser
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6 (Czech Republic).
authors.forename: Dana
authors.initials: D
authors.lastname: Hocková
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4068 (Australia).
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Wang
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6 (Czech Republic).
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6 (Czech Republic).
authors.forename: Lenka
authors.initials: L
authors.lastname: Poštová-Slavětínská
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6 (Czech Republic).
authors.forename: Eliška
authors.initials: E
authors.lastname: Procházková
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland 4051 (Australia).
authors.forename: Michael D
authors.initials: MD
authors.lastname: Edstein
authors.affiliation: Department of Drug Evaluation, Australian Army Malaria Institute, Enoggera, Brisbane, Queensland 4051 (Australia).
authors.forename: Marina
authors.initials: M
authors.lastname: Chavchich
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4068 (Australia).
authors.forename: Dianne T
authors.initials: DT
authors.lastname: Keough
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4068 (Australia). luke.guddat@uq.edu.au.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Flemingovo nám. 2, 16610 Prague 6 (Czech Republic). janeba@uochb.cas.cz.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Janeba
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D009705:Nucleosides; D063065:Organophosphonates; D007041:Hypoxanthine Phosphoribosyltransferase
keywords: 6-oxopurine; acyclic nucleoside phosphonates; malaria; phosphoramidates; phosphoribosyltransferases