Discovery of dual function acridones as a new antimalarial chemotype - PubMed (original) (raw)

. 2009 May 14;459(7244):270-3.

doi: 10.1038/nature07937. Epub 2009 Apr 8.

Martin J Smilkstein, Reto Brun, Sergio Wittlin, Roland A Cooper, Kristin D Lane, Aaron Janowsky, Robert A Johnson, Rozalia A Dodean, Rolf Winter, David J Hinrichs, Michael K Riscoe

Affiliations

Discovery of dual function acridones as a new antimalarial chemotype

Jane X Kelly et al. Nature. 2009.

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.

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Conflict of interest statement

Competing Interests statement The authors declare that they have no competing financial interests.

Figures

Figure 1.

Figure 1.

Generalized chemical structure of dual-function acridone derivatives. The rigid tricyclic aromatic acridone core promotes π-π stacking for heme binding. The side chain attachment at the central nitrogen atom provides a hydrogen bond acceptor needed for the chemosensitization function, and together with the side chain at the 6-position facilitate accumulation in the digestive vacuole (DV) via acid trapping.

Figure 2.

Figure 2.

Isobolograms of the in vitro interaction of A) T3.5/chloroquine against MDR P. falciparum strain Dd2 and chloroquine sensitive P. falciparum strain D6 (mean FIC indices are 0.72 and 0.97, respectively); B) T3.5/amodiaquine, T3.5/mefloquine, T3.5/quinine and T3.5/piperaquine combinations against MDR strain Dd2 (mean FIC indices are 0.73, 1.25, 0.50, and 0.60, respectively); C) T3.5/quinine (solid line) combination against chloroquine sensitive strain D6 and MDR strains Dd2 and 7G8 (mean FIC indices are 0.64, 0.50, and 0.49, respectively); T3.5/piperaquine (dashed line) combination against chloroquine sensitive strain D6 and MDR strains Dd2 and 7G8 (mean FIC indices are 0.66, 0.60, and 0.51, respectively). The mean FIC indices ± standard errors of the mean (S.E.M.) were derived from three independent experiments. The _x_-axis represents the FICs of quinolines, and _y_-axis represents the FICs of T3.5. The diagonal line (FIC index = 1) indicates the hypothetical additive drug effect. A concave curve (FIC index < 1) below the diagonal line typically indicates synergy of the combination, while a convex curve (FIC index > 1) above the diagonal line indicates antagonism.

Figure 3.

Figure 3.

Confocal microscopy of localized T3.5 fluorescence in two intraerythrocytic P. falciparum trophozoites. Fluorescence was determined in live _P. falciparum_-infected erythrocytes using a laser (emission line 351 nm) scanning confocal microscope. The figure shows the intrinsic fluorescence of T3.5 (blue) superimposed on the brightfield transmission image of the infected cells.

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