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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
Jazyk angličtina Země Francie
Typ dokumentu časopisecké články
- MeSH
- antimalarika chemická syntéza metabolismus farmakologie MeSH
- buněčné linie MeSH
- erytrocyty cytologie metabolismus parazitologie MeSH
- inhibitory enzymů chemie metabolismus MeSH
- léková rezistence účinky léků MeSH
- lidé MeSH
- nukleotidy chemie metabolismus MeSH
- pentosyltransferasy antagonisté a inhibitory metabolismus MeSH
- piperazin chemie MeSH
- piperidiny chemie MeSH
- Plasmodium falciparum účinky léků enzymologie MeSH
- Plasmodium vivax enzymologie MeSH
- preklinické hodnocení léčiv MeSH
- prekurzory léčiv chemická syntéza chemie metabolismus farmakologie MeSH
- protozoální proteiny antagonisté a inhibitory metabolismus MeSH
- pyrrolidiny chemie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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.
Citace poskytuje Crossref.org
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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 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 Keough, Dianne T $u School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, 4068, Australia
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