The effect of novel [3-fluoro-(2-phosphonoethoxy)propyl]purines on the inhibition of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases

Baszczynski, Ondrej, Hockova, Dana, Janeba, Zlatko, Holy, Antonin, Jansa, Petr, Dracinsky, Martin, Keough, Dianne T. and Guddat, Luke W. (2013) The effect of novel [3-fluoro-(2-phosphonoethoxy)propyl]purines on the inhibition of Plasmodium falciparum, Plasmodium vivax and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases. European Journal of Medicinal Chemistry, 67 81-89. doi:10.1016/j.ejmech.2013.06.032


Author Baszczynski, Ondrej
Hockova, Dana
Janeba, Zlatko
Holy, Antonin
Jansa, Petr
Dracinsky, Martin
Keough, Dianne T.
Guddat, Luke W.
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
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0223-5234
1768-3254
Publication date 2013-09
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2013.06.032
Open Access Status DOI
Volume 67
Start page 81
End page 89
Total pages 9
Place of publication Issy les Moulineaux, Cedex, France
Publisher Elsevier Masson
Collection year 2014
Language eng
Formatted 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. 
Keyword Malaria
Nucleoside phosphonates
Fluorine
Purines
Antimalarial Chemotherapy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 8 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 9 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 25 Oct 2013, 11:32:56 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences