| Summary: | The world suffers under the immense threat of malaria with about 1 million people dying and
a further 500 million people getting infected and debilitated by the disease each year. It has a
negative effect on the economic growth in developing countries that already battles with
political unrest, civil wars, famine and the effect of diseases like tuberculosis and HIV/AIDS.
Resistance against the first line drugs such as the quinolines and the antifolate combination
drugs makes the fight against malaria increasingly difficult and has prompted studies into
alternative chemotherapeutic treatments of the disease. An efficient strategy to develop an
effective and cheaper antimalarial compound appears to be the re–design of existing drugs
and the exploitation of known parasite–specific targets.
In our search for novel drugs with improved antimalarial properties compared to the existing
ones, we applied an emerging strategy in medicinal chemistry called hybridisation. This is the
combination of two or more active ingredients into a single chemical entity to form a hybrid
drug. The hybrid drug strategy has the potential advantage of restoring the effectiveness in
antimalaria drugs such as the quinolines and the antifolate drugs. Artemisinin based and
quinoline based hybrid drugs are demonstrative examples of the validity of such an
approach.
Chloroquine used to be the first–choice drug in malaria treatment and prophylaxis ever since
its discovery, but drug resistance has rendered it almost completely useless in treating
Plasmodium falciparum. Today, it is still widely used in treating Plasmodium vivax malaria in
resistance free areas. The historical success of the aminoquinoline antimalarial drugs
supported our decision to include the quinoline pharmacophore in our study.
Pyrimethamine has been the most widely used antimalarial antifolate drug. It is used in
malaria prophylaxis in combination with sulphonamides. Point mutations in the parasite’s dhfr
domain of the dhfr gene are severely compromising its antimalarial effectiveness.
The pharmacophores of chloroquine and pyrimethamine are a quinoline and a pyrimidine
moiety, respectively. Through hybridisation of these two pharmacophores we hoped to bring
about molecules with potent antimalarial properties and, thus restoring their antimalarial
usefulness.
In this study we aimed to synthesise a series of quinoline–pyrimidine hybrids, determine their
physicochemical properties and evaluate their antimalarial activity in comparison to that of
chloroquine and pyrimethamine.
We successfully synthesised ten quinoline–pyrimidine hybrids by connecting a quinoline and
a pyrimidine moiety via different linkers. The structures of the prepared hybrids were
confirmed by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS).
The experimental aqueous solubility of the compounds was determined to be higher at pH
5.5 than at pH 7.4 although no structure–physicochemical property could be drawn from this
investigation.
The quinoline–pyrimidine hybrids were screened in vitro alongside chloroquine and
pyrimethamine against the chloroquine–sensitive D10 strain of Plasmodium falciparum. The
ether–linked hybrids tended to be more potent than the amine–linked ones. Compound 21,
exhibited the best antimalarial activity (IC50 = 0.08 uM) of all, and possessed activity similar to
that of pyrimethamine (IC50 = 0.11 uM). None of the compounds proved to be as effective as
chloroquine (IC50 = 0.03 uM). === Thesis (MSc (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2012.
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