Discovery of dual function acridones as a new antimalarial chemotype

New ways with antimalarials The emergence of drug resistance is a continued problem in the battle against malaria. A new class of antimalarial could help to counteract that problem by making possible a novel approach to combination therapy. The dual function acridone compounds combine the haem-targeting antimalarial action of conventional antimalarial acridones with a second active region in the molecule. This boosts the efficacy of established antimalarials such as chloroquine, amodiaquine, quinine and piperaquine synergistically, in some instances overcoming prior resistance to some of these drugs in the Plasmodium falciparum parasites. Malaria drug development remains an important public health goal, especially in light of the emergence of drug resistance. Here a new class of malaria drugs is presented: an acridone derivative containing a chemosensitizing domain that may prevent the occurrence of parasite drug resistance. Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug–haem interaction as in the case of quinolines and many other drugs 1 , 2 , 3 , 4 , 5 . Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial drugs. Beyond the essential intrinsic characteristics common to deserving candidate antimalarials (high potency in vitro against pan-sensitive and multi-drug-resistant Plasmodium falciparum , efficacy and safety in vivo after oral administration, inexpensive synthesis and favourable physicochemical properties), our initial lead, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)-acridone), demonstrates unique synergistic properties. In addition to ‘verapamil-like’ chemosensitization to chloroquine and amodiaquine against quinoline-resistant parasites, T3.5 also results in an apparently mechanistically distinct synergism with quinine and with piperaquine. This synergy, evident in both quinoline-sensitive and quinoline-resistant parasites, has been demonstrated both i