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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
- Source :
- European journal of medicinal chemistry. 219
- Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Purine
Erythrocytes
Pyrrolidines
Cell Survival
Plasmodium falciparum
Drug Evaluation, Preclinical
Drug Resistance
Protozoan Proteins
01 natural sciences
Cell Line
03 medical and health sciences
chemistry.chemical_compound
Antimalarials
Structure-Activity Relationship
Piperidines
Drug Discovery
Humans
Nucleotide
Prodrugs
Pentosyltransferases
Enzyme Inhibitors
Piperazine
030304 developmental biology
Pharmacology
chemistry.chemical_classification
0303 health sciences
biology
010405 organic chemistry
Nucleotides
Organic Chemistry
Phosphoramidate
General Medicine
Prodrug
Xanthine
0104 chemical sciences
chemistry
Biochemistry
biology.protein
Phosphoribosyltransferase
Plasmodium vivax
Nucleoside
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 219
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....9a87339818d3a0a358adcf29e2026c2a