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

Frydrych, Jan; Keough, D. T.; Chavchich, M.; Travis, J.; Dračínský, Martin; Edstein, M. D.; Guddat, L. W.; Hocková, Dana; Janeba, Zlatko

doi:https://dx.doi.org/10.1016/j.ejmech.2021.113416

Number of the records: 1

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

1.

SYSNO ASEP	0542010
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	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
Author(s)	Frydrych, Jan (UOCHB-X) Keough, D. T. (AU) Chavchich, M. (AU) Travis, J. (AU) Dračínský, Martin (UOCHB-X)_{RID, ORCID} Edstein, M. D. (AU) Guddat, L. W. (AU) Hocková, Dana (UOCHB-X)_{RID, ORCID} Janeba, Zlatko (UOCHB-X)_{RID, ORCID}
Article number	113416
Source Title	European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234 Roč. 219, Jul 5 (2021)
Number of pages	18 s.
Language	eng - English
Country	FR - France
Keywords	nucleoside phosphonates ; phosphoroamidate prodrug ; HG(X)PRT ; hypoxanthine-guanine-(xanthine) phosphoribosyltransferase ; Plasmodium falciparum ; Plasmodium vivax
OECD category	Organic chemistry
R&D Projects	GA19-07707S GA ČR - Czech Science Foundation (CSF)
Method of publishing	Limited access
Institutional support	UOCHB-X - RVO:61388963
UT WOS	000646945500006
EID SCOPUS	85104345750
DOI	10.1016/j.ejmech.2021.113416
Annotation	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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2022
Electronic address	https://doi.org/10.1016/j.ejmech.2021.113416

Number of the records: 1