Details

Autor(en) / Beteiligte

• Frydrych, Jan
• Keough, Dianne T.
• Chavchich, Marina
• Travis, Jye
• Dračínský, Martin
• Edstein, Michael D.
• Guddat, Luke W.
• Hocková, Dana
• Janeba, Zlatko

Titel

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

Ist Teil von

• European journal of medicinal chemistry, 2021-07, Vol.219, p.113416-113416, Article 113416

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •Synthesis of novel acyclic nucleoside phosphonates described.•Phosphonates exhibit a broad range of Ki values (0.15–72 μM).•Most of the phosphoramidate prodrugs exhibit potent in vitro antimalarial activity (IC50 = 2.5–12.1 μM).•Compounds exhibited low cytotoxicity in the human HepG2 and NHDF cell lines.