Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F17%3A00477558" target="_blank" >RIV/61388963:_____/17:00477558 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.bmc.2017.05.048" target="_blank" >http://dx.doi.org/10.1016/j.bmc.2017.05.048</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmc.2017.05.048" target="_blank" >10.1016/j.bmc.2017.05.048</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

Popis výsledku v původním jazyce

Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N-9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower K-i values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest K-i values obtained for the two parasite enzymes were 0.1 mu M (Pf) and 0.2 mu M (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5 mu M. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300 mu M resulting in an excellent selectivity index.

Název v anglickém jazyce

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

Popis výsledku anglicky

Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N-9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower K-i values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest K-i values obtained for the two parasite enzymes were 0.1 mu M (Pf) and 0.2 mu M (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5 mu M. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300 mu M resulting in an excellent selectivity index.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GA16-06049S" target="_blank" >GA16-06049S: Inhibitory 6-oxopurin fosforibosyltransferáz založené na acyklických nukleosidfosfonátech: potenciální nové antibakteriální a antiparazitické látky</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Bioorganic & Medicinal Chemistry

ISSN

0968-0896

e-ISSN

—

Svazek periodika

25

Číslo periodika v rámci svazku

15

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

23

Strana od-do

4008-4030

Kód UT WoS článku

000406022200011

EID výsledku v databázi Scopus

2-s2.0-85020383102