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

0542010 - ÚOCHB 2022 RIV FR eng J - Journal Article
Frydrych, Jan - Keough, D. T. - Chavchich, M. - Travis, J. - Dračínský, Martin - Edstein, M. D. - Guddat, L. W. - Hocková, Dana - Janeba, Zlatko
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.
European Journal of Medicinal Chemistry. Roč. 219, Jul 5 (2021), č. článku 113416. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR(CZ) GA19-07707S
Institutional support: RVO:61388963
Keywords : nucleoside phosphonates * phosphoroamidate prodrug * HG(X)PRT * hypoxanthine-guanine-(xanthine) phosphoribosyltransferase * Plasmodium falciparum * Plasmodium vivax
OECD category: Organic chemistry
Impact factor: 7.088, year: 2021
Method of publishing: Limited access
https://doi.org/10.1016/j.ejmech.2021.113416

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.
Permanent Link: http://hdl.handle.net/11104/0319509