Synthesis of novel N-branched acyclic nucleoside phosphonates as potent and selective inhibitors of human, Plasmodium falciparum and Plasmodium vivax 6-oxopurine phosphoribosyltransferases
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22725979
DOI
10.1021/jm300662d
Knihovny.cz E-resources
- MeSH
- Antimalarials chemical synthesis chemistry pharmacology MeSH
- Hypoxanthine Phosphoribosyltransferase antagonists & inhibitors MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Malaria drug therapy MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Nucleosides chemical synthesis chemistry pharmacology MeSH
- Organophosphonates chemical synthesis chemistry pharmacology MeSH
- Pentosyltransferases antagonists & inhibitors MeSH
- Plasmodium falciparum drug effects enzymology MeSH
- Plasmodium vivax drug effects enzymology MeSH
- Drug Design MeSH
- Substrate Specificity MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antimalarials MeSH
- hypoxanthine-guanine-xanthine phosphoribosyltransferase MeSH Browser
- Hypoxanthine Phosphoribosyltransferase MeSH
- Enzyme Inhibitors MeSH
- Nucleosides MeSH
- Organophosphonates MeSH
- Pentosyltransferases MeSH
Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) is crucial for the survival of malarial parasites Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Acyclic nucleoside phosphonates (ANPs) are inhibitors of HG(X)PRT and arrest the growth of Pf in cell culture. Here, a novel class of ANPs containing trisubstituted nitrogen (aza-ANPs) has been synthesized. These compounds have a wide range of K(i) values and selectivity for human HGPRT, PfHGXPRT, and PvHGPRT. The most selective and potent inhibitor of PfHGXPRT is 9-[N-(3-methoxy-3-oxopropyl)-N-(2-phosphonoethyl)-2-aminoethyl]hypoxanthine (K(i) = 100 nM): no inhibition could be detected against the human enzyme. This compound exhibits the highest ever reported selectivity for PfHGXPRT compared to human HGPRT. For PvHGPRT, 9-[N-(2-carboxyethyl)-N-(2-phosphonoethyl)-2-aminoethyl]guanine has a K(i) of 50 nM, the best inhibitor discovered for this enzyme to date. Docking of these compounds into the known structures of human HGPRT in complex with ANP-based inhibitors suggests reasons for the variations in affinity, providing insights for the design of antimalarial drug candidates.
References provided by Crossref.org
Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects
