Malaria endemic areas not only pose a public health threat, but affects 3.3 billion people
worldwide. In 2011, estimated malaria related deaths amounted to 660 000 out of 219 million
reported cases, with 81% of these and 91% of malaria related mortality occurred in the African
region. Those most affected were pregnant women, children under the age of five and immunocompromised
individuals. Malaria is the fifth deadliest disease worldwide and accounts for the
second highest death rate in Africa, following HIV/Aids.
To combat this parasitic infection of antiquity, the ideal malaria pharmacotherapy would be a
cost effective and easily obtainable monotherapy. The malaria parasite, however, has an
intrinsic ability to develop drug resistance through various mechanisms. Widespread resistance
towards antimalarial drugs has rendered traditionally used drugs therapeutically ineffective,
hence accentuating the efficacy of the artemisinins as first line treatment option for
uncomplicated Plasmodium falciparum (P. falciparum). A devastating reality of the challenging
battle against malaria is the confirmed prolonged parasitic clearance times of the artemisinins,
despite adequate drug exposure, which emphasises the urgent need for identifying and
developing new, effective and safe therapies.
During this study, 9-aminoacridines and artemisinin-acridine hybrids were successfully
synthesised through nucleophillic substitution and their chemical structures confirmed by means
of nuclear magnetic resonance spectroscopy (NMR), high resolution mass spectroscopy
(HRMS) and infrared spectroscopy (IR). The hybrid compounds were synthesised through
microwave assisted radiation, by covalently linking the artemisinin- and amino-functionalised
acridine pharmacophores by means of a liable aminoethyl ether chain.
The target compounds were screened in vitro for antimalarial activity against both the
chloroquine sensitive (NF54) and chloroquine resistant (Dd2) strains of P. falciparum. Their
cytotoxicities were assessed against various mammalian cells of different origins, viz. the
Chinese hamster ovarian cells (CHO) from animal origin, and from human origin, hepatocellular-
(HepG2), neuroblastoma- (SH-SY5Y) and cervical cancer (HeLa) cells.
The synthesised hybrids exhibited antimalarial activity against both Plasmodium strains.
Compound 7, featuring an ethylenediamine moiety in the linker, was the most active hybrid, with
50% inhibitory concentration (IC50) values of 2.6 nM and 35.3 nM against the NF54 and Dd2
strains, respectively. It had gametocytocidal activity against the NF54 strain, comparable to
dihydroartemisinin (DHA) and artesunate (AS) and it is significantly more potent than chloroquine (CQ), whilst possessing a resistance index value of 14, indicative of a significant
loss of activity against the CQ resistant strain.
Contrary, the promising hybrid 10, containing a 2-methylpiperazine linker, had gametocytocidal
activity, comparable to CQ and was found to be six-fold more potent than CQ against the Dd2
strain, with a resistance index (RI) value of 2, whilst it further showed highly selective action
towards the parasitic cells. Compound 10 was also found to possess anticancer activity against
the HeLa cell line, comparable to DHA and AS, but fivefold higher than that of CQ, with the
same levels of hepatotoxicity and neurotoxicity.
The artemisinin-acridine hybrids displayed superior antimalarial activity, compared to the
derived 9-aminoacridines against both the Plasmodium strains. They, however, did not have the
ability to overcome resistance, reduce the toxicity of acridine, nor induce synergistic activity. The
hybrids, indeed displayed promising anticancer activity against HeLa cells. It is anticipated that
these compounds may stand as drug candidates for further investigation in the search for new
anti-cervical cancer drugs, rather than as antimalarials. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/12243 |
| Date | January 2013 |
| Creators | Joubert, Juan Paul |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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