The in vitro antiplasmodial properties of novel aminoquinolines and metal complexes of thiomethyl and methylthiomethyl ainline derivatives

Holland, Shamillah
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The spread of drug resistance in Africa to standard antimalarials has equally contributed to the burden of malaria. As a result new drug delivery targets and compounds need to be explored for malaria treatment.This could include the use of metalloVbased antimalarials and compounds capble of inducing oxidative stress in the parasite. A series of aminoquinoline and quinolinV8Vyl derivatives, as well as metal complexes of thiomethyl (MA) and methylthiomethyl (MT) aniline derivatives were evaluated for antimalarial activity using the tritiated hypoxanthine incorporation and parasite lactate dehydrogenase assay against the chloroquineVsensitive 3D7 P.# falciparum strain. The compounds were investigated to determine a possible mechanism of action through monitoring the inhibition of haemozoin formation,oxidative stress pathways, iron and copper chelating properties. The toxicity was evaluated by examining the effect on haemolysis and human kidney epithelium and erythroleukemia cells. The aminoquinoline derivatives displayed moderate antimalarial activity in comparison to quinine (IC50 value: 0.0964 ± 0.002 μM).This was theorized to have been produced through a proVoxidant effect that had no effect on the integrity of the red blood cell membrane. Compounds III+ and V, both aminoquinoline derivatives displayed antioxidant activity by scavenging of free radicals and inhibiting lipid peroxidation,possibly by their gallic acid and 8Vhydroxyquinoline components. The copper complexes of MA and MT aniline derivatives displayed promising antimalarial activity when compared to quinine with its activity directed towards the parasite and not the host red blood cells.CupMeO2MT (IC50 value: 2.66 ± 0.12 μM) and Cu4MeO2MA (IC50 value: 2.82 ± 0.38 μM) were the most active, and were theorized to have inhibited parasite growth through a proVoxidant effect. The derivatives bound to nickel and cobalt were able to scavenge free radicals,while the complexes bound to copper were able to inhibit lipid peroxidation. CupMeO2MT (IC50 value: 12.25 ± 1.97 μM) was found to be the most active in the MA and MT groups, although three fold less potent than camptothecin. This study revealed the use of multiVcomponent systems, as well as the use of complexing metals to compounds in the hope of finding novel compounds which could reval new drug targets in the field of malaria research.Further studies would need to be conducted on the possible proVoxidant effect of these compounds with a focus on the means of maintaining the hosts oxidative equilibrium.
A Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science in Medicine Johannesburg, South Africa, 2016