Synthesis of purine N-9-[2-hydroxy-3-O-(phosphonomethoxy)propyl] derivatives and their side-chain modified analogs as potential antimalarial agents

Krecmerova, Marcela, Dracinsky, Martin, Hockova, Dana, Holy, Antonín, Keough, Dianne T. and Guddat, Luke W. (2012) Synthesis of purine N-9-[2-hydroxy-3-O-(phosphonomethoxy)propyl] derivatives and their side-chain modified analogs as potential antimalarial agents. Bioorganic and Medicinal Chemistry, 20 3: 1222-1230. doi:10.1016/j.bmc.2011.12.034


Author Krecmerova, Marcela
Dracinsky, Martin
Hockova, Dana
Holy, Antonín
Keough, Dianne T.
Guddat, Luke W.
Title Synthesis of purine N-9-[2-hydroxy-3-O-(phosphonomethoxy)propyl] derivatives and their side-chain modified analogs as potential antimalarial agents
Journal name Bioorganic and Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
1464-3391
Publication date 2012-02-01
Year available 2011
Sub-type Article (original research)
DOI 10.1016/j.bmc.2011.12.034
Volume 20
Issue 3
Start page 1222
End page 1230
Total pages 9
Place of publication Oxford, United Kingdom
Publisher Pergamon
Collection year 2013
Language eng
Formatted abstract
6-Oxopurine acyclic nucleoside phosphonates (ANPs) have been shown to be potent inhibitors of hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), a key enzyme of the purine salvage pathway in human malarial parasites. These compounds also exhibit antimalarial activity against parasites grown in culture. Here, a new series of ANPs, hypoxanthine and guanine 9-[2-hydroxy-3-(phosphonomethoxy)propyl] derivatives with different chemical substitutions in the 2′-position of the aliphatic chain were prepared and tested as inhibitors of Plasmodium falciparum (Pf) HGXPRT, Plasmodium vivax (Pv) HGPRT and human HGPRT. The attachment of an hydroxyl group to this position and the movement of the oxygen by one atom distal from N 9 in the purine ring compared with 2-(phosphonoethoxy)ethyl hypoxanthine (PEEHx) and 2-(phosphonoethoxy)ethyl guanine (PEEG) changes the affinity and selectivity for human HGPRT, PfHGXPRT and PvHGPRT. This is attributed to the differences in the three-dimensional structure of these inhibitors which affects their mode of binding. A novel observation is that these molecules are not always strictly competitive with 5-phospho-α-d-ribosyl-1-pyrophosphate. 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]hypoxanthine (iso-HPMP-Hx) is a very weak inhibitor of human HGPRT but remains a good inhibitor of both the parasite enzymes with K i values of 2 μM and 5 μM for PfHGXPRT and PvHGPRT, respectively. The addition of pyrophosphate to the assay decreased the K i values for the parasite enzymes by sixfold. This suggests that the covalent attachment of a second group to the ANPs mimicking pyrophosphate and occupying its binding pocket could increase the affinity for these enzymes.
Keyword Acyclic nucleoside phosphonates
Malaria
Plasmodium falciparum
Plasmodium vivax
Hypoxanthine-guanine-(xanthine)-phosphoribosyltransferase
5-Phospho-alpha-D-ribosyl-1-pyrophosphate
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 29 December 2011.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
 
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