Nucleotide analogues containing a pyrrolidine, piperidine or piperazine ring: Synthesis and evaluation of inhibition of plasmodial and human 6-oxopurine phosphoribosyltransferases and in vitro antimalarial activity
Language English Country France Media print-electronic
Document type Journal Article
PubMed
33887682
DOI
10.1016/j.ejmech.2021.113416
PII: S0223-5234(21)00265-8
Knihovny.cz E-resources
- Keywords
- HG(X)PRT, Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase, Nucleoside phosphonates, Phosphoroamidate prodrug, Plasmodium falciparum, Plasmodium vivax,
- MeSH
- Antimalarials chemical synthesis metabolism pharmacology MeSH
- Cell Line MeSH
- Erythrocytes cytology metabolism parasitology MeSH
- Enzyme Inhibitors chemistry metabolism MeSH
- Drug Resistance drug effects MeSH
- Humans MeSH
- Nucleotides chemistry metabolism MeSH
- Pentosyltransferases antagonists & inhibitors metabolism MeSH
- Piperazine chemistry MeSH
- Piperidines chemistry MeSH
- Plasmodium falciparum drug effects enzymology MeSH
- Plasmodium vivax enzymology MeSH
- Drug Evaluation, Preclinical MeSH
- Prodrugs chemical synthesis chemistry metabolism pharmacology MeSH
- Protozoan Proteins antagonists & inhibitors metabolism MeSH
- Pyrrolidines chemistry MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Antimalarials MeSH
- hypoxanthine-guanine-xanthine phosphoribosyltransferase MeSH Browser
- Enzyme Inhibitors MeSH
- Nucleotides MeSH
- Pentosyltransferases MeSH
- Piperazine MeSH
- Piperidines MeSH
- Prodrugs MeSH
- Protozoan Proteins MeSH
- pyrrolidine MeSH Browser
- Pyrrolidines MeSH
Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of Ki values between 0.15 and 72 μM. The corresponding phosphoramidate prodrugs, able to cross cell membranes, have been synthesized and evaluated in a P. falciparum infected human erythrocyte assay. Of the eight prodrugs evaluated seven exhibited in vitro antimalarial activity with IC50 values within the range of 2.5-12.1 μM. The bis-phosphoramidate prodrug 13a with a mean (SD) IC50 of 2.5 ± 0.7 μM against the chloroquine-resistant P. falciparum W2 strain exhibited low cytotoxicity in the human hepatocellular liver carcinoma (HepG2) and normal human dermal fibroblasts (NHDF) cell lines at a concentration of 100 μM suggesting good selectivity for further structure-activity relationship investigations.
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