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 drugs1,2,3,4,5. 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 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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Acknowledgements
We thank D. Kyle for the gift of P. falciparum parasite Tm90-C2B, and the Malaria Research and Reference Resource Center for supplying P. falciparum parasites D6, Dd2 and 7G8. We thank A. P. Waters and C. J. Janse for the donation of GFP-labelled P. berghei strain ANKA. We thank L. Jones-Brando and R. Yolken for the cytotoxicity (HFF) data. We are grateful to A. Cornea for the confocal imaging. We thank K. Liebman, C. Hudson, S. Burgess and D. Peyton for compound characterization. We acknowledge financial support from the Merit Review Program of the Department of Veterans Affairs. United States patent applications have been filed by the US Department of Veterans Affairs to protect the intellectual property described in this report.
Author Contributions J.X.K. contributed to drug design, synthesis, in vitro screening, in vitro drug combination studies, haemozoin inhibition assays, and manuscript preparation. M.J.S. contributed to in vivo testing in the P. yoelii murine model, in vitro drug combination studies, confocal imaging, and manuscript preparation. R.B. and S.W. contributed to in vivo testing in the P. berghei murine model. R.A.C. and K.D.L. contributed to examination of the PfCRT mutant lines. A.J. and R.A.J. contributed to biogenic amine studies. R.W. and R.A.D. assisted with synthesis. D.J.H. assisted with in vivo screening in the P. yoelii murine model. M.K.R. contributed to drug design and review of the manuscript.
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Kelly, J., Smilkstein, M., Brun, R. et al. Discovery of dual function acridones as a new antimalarial chemotype. Nature 459, 270–273 (2009). https://doi.org/10.1038/nature07937
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DOI: https://doi.org/10.1038/nature07937
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