title: The effect of novel [3-fluoro-(2-phosphonoethoxy)propyl]purines on the inhibition of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases.
abstract: Protozoan parasites from the Plasmodiidae family are the causative agents of malaria. Inhibition of hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) has been suggested as a target for development of new anti-malarial therapeutics. Acyclic nucleoside phosphonates (ANPs) are potent and selective inhibitors of plasmodial HG(X)PRTs. A new series of ANPs, based on the chemical structure and inhibitory activity of three ANPs, 2-(phosphonoethoxy)ethyl with either guanine or hypoxanthine as the base (PEEG and PEEHx) and 3-hydroxy-2-(phosphonomethoxy)propyl with guanine as the base (HPMPG), were prepared. These compounds are stereoisomers of 3-fluoro-(2-phosphonoethoxy)propyl (FPEPs) and 3-fluoro-(2-phosphonomethoxy)propyl (FPMPs) analogues. Both the (R)- and (S)-isomers of these fluorinated derivatives have higher Ki values (by 10- to 1000-fold) for human HGPRT and Plasmodium falciparum HGXPRT than the non-fluorinated ANPs. Possible explanations for these changes in affinity are proposed based on docking studies using the known crystal structures of human HGPRT in complex with PEEG.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-166 10 Prague 6, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Baszczyňski
authors.forename: Dana
authors.initials: D
authors.lastname: Hocková
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Janeba
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.forename: Petr
authors.initials: P
authors.lastname: Jansa
authors.forename: Martin
authors.initials: M
authors.lastname: Dračínský
authors.forename: Dianne T
authors.initials: DT
authors.lastname: Keough
authors.forename: Luke W
authors.initials: LW
authors.lastname: Guddat
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects*; D010966:Plasmodium vivax / Q000187:drug effects*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C587477:(3-fluoro-(2-phosphonoethoxy)propyl)purine; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D011687:Purines; D010430:Pentosyltransferases; C083867:hypoxanthine-guanine-xanthine phosphoribosyltransferase
keywords: FPEP; FPMP; Fluorine; HG(X)PRT; Malaria; Nucleoside phosphonates; Purines