Synthesis, characterisation and antimalarial activity of quinoline–pyrimidine hybrids / Izak Stefanus Pretorius

• Main Author: Pretorius, Izak Stefanus
• Published: North-West University 2013
• Online Access: http://hdl.handle.net/10394/8105

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.