Discovery of dual function acridones as a new antimalarial chemotype

Abstract

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. 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 in vitro and in vivo. In summary, this innovative acridone design merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations.

Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine‐Resistant Plasmodium falciparum

“…Chloroquine chemosensitizers, also known as chloroquine-resistance-reversing agents, are thought to interact with PfCRT in such a way that drug efflux is impeded. [18,19] Compounds 7 described here match relevant structural factors of chloroquine-chemosensiziting agents recently reported by Kelly [9] and Lavrado, [20] such as a hydrogenbond acceptor (nitrogen) or aminobutyl chains between the heterocyclic core of the compound and its N-substituted terminal amine. Therefore, we cannot rule out that conjugates 7 act also through this mechanism.…”

“…[7] Additionally, it is known that a basic nitrogen together with a flexible polymethylene chain linked to the aminoquinoline core favor drug accumulation in the acidic parasite digestive vacuole and, consequently, have a positive effect of the antiplasmodial activity of the compound. [9] Therefore, we designed second-generation conjugates 7, where both the chloroquinoline and cinnamoyl cores were preserved, but where the rigid and hydrophilic dipeptide spacer of first-generation conjugates 5 has been replaced by a flexible and more hydrophobic butyl chain, which also increases the overall basicity of the compounds.…”

New approaches in antimalarial drug discovery and development: a review

“…The hybrid compound comprises dual functions and, as in acridone hybrid molecules, the drug is based on the aminoquinoline ring. The acridone T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)-acridone) targets drug-resistant strains at nanomolar concentrations and represents an innovative strategy for developing antimalarial drugs (Kelly et al 2009). …”

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

“…Thus, a role for solution association cannot necessarily be ruled out for all series of 4-aminoquinoline compounds. Finally, the correlation equations permit the prediction of both log K and log BHIA 50 for these series of [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] aminoquinolines. Interestingly, they do not suggest that the lipophilicity of the group X plays a major role in -hematin inhibition.…”