Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their prodrugs as antimalarial agents

Keough, Dianne T., Hockova, Dana, Janeba, Zlatko, Wang, Tzu-Hsuan, Naesens, Lieve, Edstein, Michael D., Chavchich, Marina and Guddat, Luke W. (2015) Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their prodrugs as antimalarial agents. Journal of Medicinal Chemistry, 58 2: 827-846. doi:10.1021/jm501416t


Author Keough, Dianne T.
Hockova, Dana
Janeba, Zlatko
Wang, Tzu-Hsuan
Naesens, Lieve
Edstein, Michael D.
Chavchich, Marina
Guddat, Luke W.
Title Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their prodrugs as antimalarial agents
Formatted title
Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their prodrugs as antimalarial agents
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1520-4804
0022-2623
Publication date 2015-01-22
Year available 2014
Sub-type Article (original research)
DOI 10.1021/jm501416t
Open Access Status
Volume 58
Issue 2
Start page 827
End page 846
Total pages 20
Place of publication Washington, DC United States
Publisher American Chemical Society
Collection year 2015
Language eng
Formatted abstract
Hypoxanthine–guanine–[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for antimalarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT), with Ki values as low as 0.08 and 0.01 μM for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza-ANPs exhibit antimalarial activity against Pf lines with IC50 values (0.8–6.0 μM) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors, allowing them to adapt to fit into three binding pockets of the enzyme(s).
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 11 Dec 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
 
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