Abstract
Background:
Each year roughly 800 000 people die of malaria, with 95% being African children.
The shortcomings of the current drugs and the emergence of P. falciparum resistance to the artemisinin class of compounds warrant the search for new classes
or derivatives. In search for such compounds, a series of 10β-aminoquinolinylethylethers
of artemisinin, previously synthesized from this laboratory were screened for antimalarial
activity against both the chloroquine-susceptible 3D7 and -resistant K1 strains of
P. falciparum. Their cytotoxicity was also assessed against HEK 293 and HepG2 cell lines.
Methods:
The parasitic and mammalian cells were incubated with compounds at various concentrations
for 72 h. The antimalarial activity was determined using SYBR Green I-based fluorescence.
For cytotoxicity determination, cells were grown to confluence and CellTiter-Glo luminescent
cell viability assay was used.
Results:
All derivatives proved to be active against both strains with good selectivity towards
the parasitic cells. The derivative 11 featuring 2 artemisinin moieties and an aminoethylpiperazine linker was the most
active of all. It possessed 17- and 166-fold more potency than artemether against
3D7 (EC50: 9.5 vs. 166 nM) and K1 (10.9 vs. 1723.3 nM), respectively, while was found to be as potent as artesunate against both
strains.
Conclusion:
Derivative 11 stands as a good candidate to be further investigated primarily in vitro in comparison
with an equimolar combination of chloroquine (CQ) and artemisinin to ascertain its
advantages, if any, over the combination.
Key words
malaria -
P. falciparum
- selectivity
