The artemisinins have been a game changer in antimalarial chemotherapy for the past two decades. The current picture, however, shows that artemisinin resistance has created a situation where new drugs are a priority. This resistance initially manifested itself as extended parasite clearance times but has subsequently resulted in reduced overall efficacy as well as artemisinin based combination therapy resistance.
The efficacy of many existing antimalarials implicates ferrous iron in some manner – both the quinolines and the artemisinins being examples where interaction with ferrous iron has been implicated in the mode of action. This gives rise to a key question: is it possible to utilise alternative interactions with ferrous iron that will result in potent antimalarial compounds without cross-resistance with the artemisinins?
We now report on a series of mechanistically discrete antimalarial compounds (i.e., redox iron chelators) with IC50s<15 nM against drug-resistant Plasmodium falciparum lines and potent schizont maturation inhibition activity against P. berghei in vitro (IC50 ~ 50 nM) as well as in vivo oral efficacy in the P. berghei-mouse model (ED50 = 1.4 mg/kg/day in the Peters 4-day suppression test) comparable to artesunate. Importantly, these compounds do not exhibit cross resistance with the artemisinins and our pharmacokinetic studies show lengthy blood elimination half-lives of about 2 days. These favourable parasitological and pharmacological findings suggest that this class of compound has the key attributes for further preclinical development. We discuss the development and characterisation of these compounds to date and their ongoing potential for the treatment of malaria.