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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
J. Frydrych, DT. Keough, M. Chavchich, J. Travis, M. Dračínský, MD. Edstein, LW. Guddat, D. Hocková, Z. Janeba
Language English Country France
Document type Journal Article
- 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
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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- $a Frydrych, Jan $u The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, CZ-16610 Prague 6, Czech Republic
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- $a 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 / $c J. Frydrych, DT. Keough, M. Chavchich, J. Travis, M. Dračínský, MD. Edstein, LW. Guddat, D. Hocková, Z. Janeba
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- $a 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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