The in vitro antiplasmodial properties of novel aminoquinolines and metal complexes of thiomethyl and methylthiomethyl ainline derivatives
Date
2016-10-14
Authors
Holland, Shamillah
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Abstract
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.
Description
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