Conference Agenda

The treatment of malaria, an infectious disease caused by Plasmodium parasites, relies on numerous chemotherapies that are hampered by drug resistance. New antimalarial drugs with mechanisms of action different to currently used drugs are required to combat Plasmodium drug resistance. Robenidine is an antiparasitic drug with modest activity against P. falciparum (50% growth inhibitory concentration; IC₅₀ 0.76 µM) and unknown mode of action. To aid in the identification of new antimalarial drug candidates, a library of robenidine analogues was assessed for improved activity and selectivity for P. falciparum over mammalian cells. Multiple compounds with hit and early-lead activity and selectivity were identified, including NCL123 and NCL146, which demonstrated P. falciparum IC₅₀ values <0.1 µM and selectivity indices of >100. While in vivo studies with NCL123 and NCL146 demonstrated that further optimisation is needed to facilitate cures in mice infected with P. berghei ANKA, both compounds were well-tolerated and structural activity relationships have been useful in identifying avenues to improve this activity. Preliminary mode of action studies with NCL146 also suggest that this compound may have an unexploited mode of action associated with lipid biosynthesis, membrane function and cellular trafficking.