The effect of 7-chloroquinoline derivatives on the life cycle of the malaria parasite
With the widespread resistance to current antimalarials and the great burden of malaria, the aim of this study was to determine the antimalarial activity of novel derivatives against the Plasmodium falciparum NF54 strain alone and in combination with quinine using the pLDH assay. The derivatives were designed such that they maintained the core chloroquinoline structure with known antimalarial activity with the addition of further scaffolds with a different mechanism of action in an attempt to produce compounds with good antimalarial activity with a lower probability of developing resistance. The twenty-seven 7-chloroquinolin-4-yl piperazine-1-yl acetamide (CQPA) derivatives and the nine 4-((7-chloroquinolin-4-yl) piperazine-1-yl) pyrrolidin-2-yl) methanone (CQPPM) derivatives all possessed antimalarial activity with 4 and 8 derivatives from each class respectively showed inhibitory activity below 10 µM. The most active derivative from each set of derivatives, CQPA-26 and CQPPM-9 displayed good antimalarial activity with IC50 values of 1.29 µM and 1.42 µM, respectively compared to the standard antimalarial, quinine (IC50: 0.18 µM). The two most active derivatives displayed drug-like properties with favourable ionisation properties to confirm its ability to accumulate in the parasites’ digestive vacuole. In combination with quinine, these derivatives displayed synergistic and additive interactions, respectively. Morphological studies were carried out over a period of 48 hours to identify which parasite stage was most sensitive to the most active derivative from each class of derivatives. Both derivatives proved to show similar schizonticidal activity as the standard quinine with a lag in progression from the trophozoite stage. The inability to induce haemolysis indicated that the derivatives acted against the parasite and not the host red blood cell (<1% lysis), conferring a good safety profile. The low toxic nature of the derivatives was further demonstrated with the minimal toxicity towards human embryonic kidney epithelial cells and no effect on Artemia fransiscana brine shrimp viability (<5% lethality). Although the cyclopropyl and methyl substituted derivatives displayed good activity towards the intra-erythrocytic parasite, all the derivatives lacked larvicidal activity towards Anopheles arabiensis (mortality range: 0 - 5%). The derivatives showed no effect on the morphological structure of the Artemia fransiscana brine shrimp and the An. arabiensis larvae. This study highlights the good antimalarial activity of these derivatives coupled with a favourable safety profile as antimalarial agents and not larvicides. The introduction of less bulky side chains proved to show a greater antimalarial activity against Plasmodium falciparum.
A dissertation submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in the fulfilment of the requirements for the degree of Master of Science in Medicine, 2017