Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

Hockova, Dana, Janeba, Zlatko, Naesens, Lieve, Edstein, Michael D., Chavchich, Marina, Keough, Dianne T. and Guddat, Luke W. (2015) Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases. Bioorganic and Medicinal Chemistry, 23 17: 5502-5510. doi:10.1016/j.bmc.2015.07.038

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Author Hockova, Dana
Janeba, Zlatko
Naesens, Lieve
Edstein, Michael D.
Chavchich, Marina
Keough, Dianne T.
Guddat, Luke W.
Title Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases
Journal name Bioorganic and Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
1464-3391
Publication date 2015-07-27
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.bmc.2015.07.038
Open Access Status File (Author Post-print)
Volume 23
Issue 17
Start page 5502
End page 5510
Total pages 9
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon Press
Collection year 2016
Language eng
Formatted abstract
Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors—the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads.
Keyword Nucleotide analogues
Enzyme inhibitors
Malaria
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Thu, 20 Aug 2015, 10:18:32 EST by Prycilla Rehm on behalf of School of Chemistry & Molecular Biosciences