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
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
33887682
DOI
10.1016/j.ejmech.2021.113416
PII: S0223-5234(21)00265-8
Knihovny.cz E-zdroje
- Klíčová slova
- HG(X)PRT, Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase, Nucleoside phosphonates, Phosphoroamidate prodrug, Plasmodium falciparum, Plasmodium vivax,
- 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
- Názvy látek
- antimalarika MeSH
- hypoxanthine-guanine-xanthine phosphoribosyltransferase MeSH Prohlížeč
- inhibitory enzymů MeSH
- nukleotidy MeSH
- pentosyltransferasy MeSH
- piperazin MeSH
- piperidiny MeSH
- prekurzory léčiv MeSH
- protozoální proteiny MeSH
- pyrrolidine MeSH Prohlížeč
- pyrrolidiny 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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