Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1' position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1' chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)-enantiomers. Two ANPs, with Ki values of 0.39 μM and 0.57 μM, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites.
- MeSH
- adeninfosforibosyltransferasa antagonisté a inhibitory metabolismus MeSH
- adenosinmonofosfát chemická syntéza chemie farmakologie MeSH
- antiprotozoální látky chemická syntéza chemie farmakologie MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- molekulární struktura MeSH
- nukleosidy chemická syntéza chemie farmakologie MeSH
- parazitické testy citlivosti MeSH
- Trypanosoma brucei brucei účinky léků enzymologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články 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.
- 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
Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel α-branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC50 >10 μm) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5-haloanthraniloyl-substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 362 nm.
- MeSH
- adenylátcyklasový toxin antagonisté a inhibitory MeSH
- antigeny bakteriální MeSH
- bakteriální proteiny antagonisté a inhibitory MeSH
- bakteriální toxiny antagonisté a inhibitory MeSH
- buněčné linie MeSH
- inhibitory adenylylcyklasy chemie farmakologie MeSH
- konformace proteinů MeSH
- lidé MeSH
- makrofágy cytologie účinky léků MeSH
- nukleosidy chemie farmakologie MeSH
- organofosfonáty chemie farmakologie MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
A pyrolysis of compost for the production of syngas with an explicit H2/CO = 2 or H2/CO = 3 was investigated in this study. The composts were obtained from nonhybrid (perennial) grasses (NHG) and hybrid (perennial) grasses (HG). Discrepancies in H2 evolution profiles were found between NHG and HG composts. In addition, positive correlations for NHG composts were obtained between (i) H2 yield and lignin content, (ii) H2 yield and potassium content, and (iii) CO yield and cellulose content. All composts resulted in H2/CO = 2 and five of the nine composts resulted in H2/CO = 3. Exceptionally large higher heating values (HHVs) of pyrolysis gas, very close to HHVs of feedstock, were obtained for composts made from mountain brome (MB, 16.23 MJ/kg), hybrid Becva (FB, 16.45 MJ/kg), and tall fescue (TF, 17.43 MJ/kg). The MB and FB composts resulted in the highest syngas formation with H2/CO = 2, whereas TF compost resulted in the highest syngas formation with H2/CO = 3.
