Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as chloroquine (CQ) and now the established tolerance towards the widely used artemisinins, an immense need exists for identifying and developing new and effective antiplasmodial drugs. In search for such new antimalarial drugs, three chalcone based series of compounds were prepared and investigated during this study. The first series (Chapter 3) comprised 4-aminoquinolinyl-chalcone amides, which were synthesized through amidation of carboxylic acid-functionalised chalcone with aminoquinolines, using 1,1'-carbonyldiimidazole (CDI) as coupling agent. These compounds were screened alongside CQ against the CQ sensitive (3D7) and CQ resistant (W2) strains of P. falciparum. Cytotoxicity was assessed against the WI-38 cell line. The amide, featuring the 1,6-diaminohexane linker, was found the most active of all these new novel compounds tested. It was found to be as potent as CQ against 3D7, while displaying a two-fold higher activity than CQ against the W2 strain, coupled with good selective antimalarial activity (SI = 435) towards the parasitic cells. The second series (Chapter 4) consisted of aminoferrocenyl-chalcone amides, synthesized through condensation of a chalcone with an aminoferrocenyl. These compounds were screened against the 3D7, and antifolate- and CQ resistant (FCR3) strains of P. falciparum and cytotoxicity was determined against the WI-38 line. The most active compound of this series was the amide, containing the 1,2-diaminoethane linker, which showed 130- and 42 times less potency than CQ against the 3D7 and W2 strains, respectively. The third series of antimalarials (Chapter 5) involved dihydroartemisinyl-chalcone esters, synthesized through esterification of chalcones with DHA. These compounds were screened against 3D7 and W2 strains of P. falciparum, while the cytotoxicity was determined against the WI-38 line. Those esters featuring oxygenated aryl rings were three- to four-fold more potent than current clinically used artesunate against both P. falciparum strains. They were also screened in vitro against a panel of three cancer cell lines consisting of TK-10, UACC-62 and MCF-7. Thermogravimetric analysis revealed that the targeted hybrids were all thermally more stable than DHA as a result of the presence of the chalcone moiety in their structures. This could prove beneficial to the high temperature storage conditions that prevail in most malaria endemic countries. This study resulted in a number of compounds with varying antiplasmodial activity ranges. The compounds in series 3 were overall the most active, due to the incorporation of the highly active dihydroartemisinin pharmacophore. The chalcone moiety, especially, demonstrated a large scope for future development, owing to the ease of synthesis and the relatively low costs involved. The most active compounds of the three series could serve as potential lead compounds in the future development of more effective antimalarial drugs. / PhD (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Malaria is endemic in 106 countries worldwide. This disease is caused by a parasite from the genus Plasmodium. Of the five species that infect humans, Plasmodium falciparum is the most virulent, with over three billion people at risk and around 660 000 deaths reported in 2011. Of these deaths, 91% were in the African region, while 86% were children under the age of five. In light of the widespread development of resistance by malaria parasites against the classic antimalarial drugs, such as chloroquine (CQ) and now the established tolerance towards the widely used artemisinins, an immense need exists for identifying and developing new and effective antiplasmodial drugs. In search for such new antimalarial drugs, three chalcone based series of compounds were prepared and investigated during this study. The first series (Chapter 3) comprised 4-aminoquinolinyl-chalcone amides, which were synthesized through amidation of carboxylic acid-functionalised chalcone with aminoquinolines, using 1,1'-carbonyldiimidazole (CDI) as coupling agent. These compounds were screened alongside CQ against the CQ sensitive (3D7) and CQ resistant (W2) strains of P. falciparum. Cytotoxicity was assessed against the WI-38 cell line. The amide, featuring the 1,6-diaminohexane linker, was found the most active of all these new novel compounds tested. It was found to be as potent as CQ against 3D7, while displaying a two-fold higher activity than CQ against the W2 strain, coupled with good selective antimalarial activity (SI = 435) towards the parasitic cells. The second series (Chapter 4) consisted of aminoferrocenyl-chalcone amides, synthesized through condensation of a chalcone with an aminoferrocenyl. These compounds were screened against the 3D7, and antifolate- and CQ resistant (FCR3) strains of P. falciparum and cytotoxicity was determined against the WI-38 line. The most active compound of this series was the amide, containing the 1,2-diaminoethane linker, which showed 130- and 42 times less potency than CQ against the 3D7 and W2 strains, respectively. The third series of antimalarials (Chapter 5) involved dihydroartemisinyl-chalcone esters, synthesized through esterification of chalcones with DHA. These compounds were screened against 3D7 and W2 strains of P. falciparum, while the cytotoxicity was determined against the WI-38 line. Those esters featuring oxygenated aryl rings were three- to four-fold more potent than current clinically used artesunate against both P. falciparum strains. They were also screened in vitro against a panel of three cancer cell lines consisting of TK-10, UACC-62 and MCF-7. Thermogravimetric analysis revealed that the targeted hybrids were all thermally more stable than DHA as a result of the presence of the chalcone moiety in their structures. This could prove beneficial to the high temperature storage conditions that prevail in most malaria endemic countries. This study resulted in a number of compounds with varying antiplasmodial activity ranges. The compounds in series 3 were overall the most active, due to the incorporation of the highly active dihydroartemisinin pharmacophore. The chalcone moiety, especially, demonstrated a large scope for future development, owing to the ease of synthesis and the relatively low costs involved. The most active compounds of the three series could serve as potential lead compounds in the future development of more effective antimalarial drugs. / PhD (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014