Poster Presenter

Artemisinin Prodrugs as More Effective Antimalarials
JC Breytenbach
South Africa

Malaria is one of the most widespread diseases in the world, affecting some 300-500 million people of which 1-2 million, mostly young children, die every year. The rapidly escalating prevalence of drug-resistant strains of Plasmodium falciparum, the high cost of conventional antimalarial medicines and the small number of widely available chemoprophylactic and chemotherapeutic agents emphasise the urgent need for safe and effective new therapies.

Artemisinin and its derivatives are potential effective antimalarial drugs for their high potency and lack of evidence of resistance, but their usefulness is unfortunately hampered by a short circulation half-life (typically 1 - 2 hours).

By using biofissionable linkages to chemically bind artemisinin to different molecular moieties various prodrugs can be prepared. In the body the linkage in the prodrug is cleaved at different rates releasing the two components over a prolonged time period. By using different types of chemical bonds in the linkers, the rate of biological release can be controlled. Problems like short drug half-life, poor patient compliance, drug resistance and high cost of treatment may be overcome in this way.

We have synthesised a series of artemisinin prodrugs of two different types, viz. (a) artemisinin-quinoline mutual prodrugs and (b) artemisinin analogue prodrugs. In the first series dihydroartemisinin was chemically linked through carbamate or carbonate bonds to known quinoline antimalarial drugs like amodiaquine, lumefantrine, mefloquine, quinine, primaquine, pyronaridine, or tafenoquinine to form the mutual prodrugs consisting of two antimalarial moieties. In the second series dihydroartemisinin was chemically linked through amine, amide, carbamate, carbonate, ether or ester bonds to a series of heterocyclic entities (mostly the pharmacophores of the quinoline antimalarial drugs named above) to give artemisinin analogue prodrugs. The structures of the prepared compounds were confirmed by physical techniques like nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS) and infrared sectrometry (IR).

The in vitro antiplasmodial activity of the prepared compounds against cultures of Plasmodium falciparum (CQ sensitive and CQ resistant) is determined by i) the parasite lactate dehydrogenase assay and, ii) FACS based assay in combination with automated liquid handling. The IC50-values are obtained using a non-linear dose-response curve fitting analysis via GraphPad Prism v.4.0 software. Cytotoxicity is determined by using the MTT-assay as measure of growth and chemosensitivity. In vivo antimalarial activity is determined in the C57B1/6 mouse strain infected with Plasmodium berghei. The pharmacokinetic properties and Formation Rate Limited metabolite kinetics in the mouse model with artemisinin as reference give the half-lifes of the new compounds. These results will be presented.