Synthesis and in vitro biological evaluation of aminoacridines and artemisinin–acridine hybrids

During this study, a series of 9-aminoacridine and artemisinin–acridine hybrids were synthesized and screened in vitro for antimalarial activity against both chloroquine sensitive (NF54) and chloroquine resistant (Dd2) strains of Plasmodium falciparum and their cytotoxicity, apoptosis and anticancer...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2014-06, Vol.56, p.16-27
Main Authors: Joubert, Juan P., Smit, Frans J., du Plessis, Lissinda, Smith, Peter J., N’Da, David D.
Format: Article
Language:English
Subjects:
Acridine
Acridines - chemical synthesis
Acridines - chemistry
Acridines - pharmacology
Animals
Antimalarials - chemical synthesis
Antimalarials - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Artemisinin
Artemisinins - chemistry
Artemisinins - pharmacology
Cell Line, Tumor
Cell Survival - drug effects
CHO Cells
Cricetulus
Cytotoxicity
Humans
Hybrids
Malaria
Plasmodium falciparum - drug effects
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Summary:During this study, a series of 9-aminoacridine and artemisinin–acridine hybrids were synthesized and screened in vitro for antimalarial activity against both chloroquine sensitive (NF54) and chloroquine resistant (Dd2) strains of Plasmodium falciparum and their cytotoxicity, apoptosis and anticancer activity were assessed against various mammalian cells. During this study, 9-aminoacridine and artemisinin–acridine hybrid compounds were synthesized and the in vitro for antimalarial activity against both the chloroquine sensitive but also gametocytocidal strain (NF54), and chloroquine resistant (Dd2) strains of Plasmodium falciparum was determined. In vitro cytotoxicity against CHO cells, apoptosis of HepG2 and SH-SY5Y as well as anticancer activity against HeLa cell lines were assessed. The hybrids were synthesized, using a microwave-assisted radiation method by covalently linking artemisinin and acridine pharmacophores by means of a liable, aminoethyl ether linker. The synthesized compounds were found active against both the Plasmodium strains and displayed superior selective toxicity towards the parasitic cells. Hybrid 7, however, containing ethylenediamine linker, proved the most active of all of the synthesized compounds. It had seven-fold higher antigametocytocidal activity compared to chloroquine and was also found to be seven-fold more potent than chloroquine against the Dd2 strain, with highly selective action towards the parasitic cells. This hybrid also showed favourable anti-cancer activity against the HeLa cells, three- and eight-fold higher than those of chloroquine and melphalan, respectively. This hybrid may therefore stand as drug candidate for further investigation in the search for new and effective drugs against malaria and cervical cancer.
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2014.01.014