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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 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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Figure 1: Generalized chemical structure of dual-function acridone derivatives.
Figure 2: The in vitro interactions of T3.5 with other antimalarials.
Figure 3: Confocal microscopy of localized T3.5 fluorescence in two intraerythrocytic P. falciparum trophozoites.

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References

  1. Yayon, A., Cabantchik, Z. I. & Ginsburg, H. Identification of the acidic compartment of Plasmodium falciparum-infected human erythrocytes as the target of the antimalarial drug chloroquine. EMBO J. 3, 2695–2700 (1984)

    Article  CAS  Google Scholar 

  2. Olliaro, P. L. & Goldberg, D. E. The Plasmodium digestive vacuole: metabolic headquarters and choice drug target. Parasitol. Today 11, 294–297 (1995)

    Article  CAS  Google Scholar 

  3. Sullivan, D. J., Gluzman, I. Y., Russell, D. G. & Goldberg, D. E. On the molecular mechanism of chloroquine’s antimalarial action. Proc. Natl Acad. Sci. USA 93, 11865–11870 (1996)

    Article  ADS  CAS  Google Scholar 

  4. Wellems, T. E. Plasmodium chloroquine resistance and the search for a replacement antimalarial drug. Science 298, 124–126 (2002)

    Article  ADS  CAS  Google Scholar 

  5. Kumar, S., Guha, M., Choubey, V., Maity, P. & Bandyopadhyay, U. Antimalarial drugs inhibiting hemozoin (β-hematin) formation: a mechanistic update. Life Sci. 80, 813–828 (2007)

    Article  CAS  Google Scholar 

  6. Krugliak, M., Zhang, J. & Ginsburg, H. Intraerythrocytic Plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins. Mol. Biochem. Parasitol. 119, 249–256 (2002)

    Article  CAS  Google Scholar 

  7. Pagola, S., Stephens, P. W., Bohle, D. S., Kosar, A. D. & Madsen, S. K. The structure of malaria pigment β-haematin. Nature 404, 307–310 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Egan, T. J. Haemozoin formation. Mol. Biochem. Parasitol. 157, 127–136 (2008)

    Article  CAS  Google Scholar 

  9. Foley, M. & Tilley, L. Quinoline antimalarials: mechanisms of action and resistance. Int. J. Parasitol. 27, 231–240 (1997)

    Article  CAS  Google Scholar 

  10. Fitch, C. D. Chloroquine resistance in malaria: a deficiency of chloroquine binding. Proc. Natl Acad. Sci. USA 64, 1181–1187 (1969)

    Article  ADS  CAS  Google Scholar 

  11. Krogstad, D. J. et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 238, 1283–1285 (1987)

    Article  ADS  CAS  Google Scholar 

  12. Fidock, D. A. et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6, 861–871 (2000)

    Article  CAS  Google Scholar 

  13. Cooper, R. A. et al. Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum . Mol. Pharmacol. 61, 35–42 (2002)

    Article  CAS  Google Scholar 

  14. Martin, S. K., Oduola, A. M. & Milhous, W. K. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 235, 899–901 (1987)

    Article  ADS  CAS  Google Scholar 

  15. van Schalkwyk, D. A. & Egan, T. J. Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum . Drug Resist. Updat. 9, 211–226 (2006)

    Article  CAS  Google Scholar 

  16. Kelly, J. X. et al. Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum . Antimicrob. Agents Chemother. 51, 4133–4140 (2007)

    Article  CAS  Google Scholar 

  17. Bhattacharjee, A. K., Kyle, D. E. & Vennerstrom, J. L. Structural analysis of chloroquine resistance reversal by imipramine analogs. Antimicrob. Agents Chemother. 45, 2655–2657 (2001)

    Article  CAS  Google Scholar 

  18. Bhattacharjee, A. K., Kyle, D. E., Vennerstrom, J. L. & Milhous, W. K. A 3D QSAR pharmacophore model and quantum chemical structure—activity analysis of chloroquine(CQ)-resistance reversal. J. Chem. Inf. Comput. Sci. 42, 1212–1220 (2002)

    Article  CAS  Google Scholar 

  19. Fivelman, Q. L., Adagu, I. S. & Warhurst, D. C. Modified fixed-ratio isobologram method for studying in vitro interactions between atovaquone and proguanil or dihydroartemisinin against drug-resistant strains of Plasmodium falciparum . Antimicrob. Agents Chemother. 48, 4097–4102 (2004)

    Article  CAS  Google Scholar 

  20. Waller, K. L. et al. Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter. J. Biol. Chem. 278, 33593–33601 (2003)

    Article  CAS  Google Scholar 

  21. Cooper, R. A., Hartwig, C. L. & Ferdig, M. T. pfcrt is more than the Plasmodium falciparum chloroquine resistance gene: a functional and evolutionary perspective. Acta Trop. 94, 170–180 (2005)

    Article  CAS  Google Scholar 

  22. Cooper, R. A. et al. Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine. Mol. Microbiol. 63, 270–282 (2007)

    Article  CAS  Google Scholar 

  23. World Health Organization Guidelines for the Treatment of Malaria. WHO/HTM/MAL/2006.1108 (WHO, 2006)

    Google Scholar 

  24. Biot, C. & Chibale, K. Novel approaches to antimalarial drug discovery. Infect. Disord. Drug Targets 6, 173–204 (2006)

    Article  CAS  Google Scholar 

  25. Egan, T. J. & Kaschula, C. H. Strategies to reverse drug resistance in malaria. Curr. Opin. Infect. Dis. 20, 598–604 (2007)

    Article  CAS  Google Scholar 

  26. Biot, C. et al. Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity. Mol. Pharm. 2, 185–193 (2005)

    Article  CAS  Google Scholar 

  27. Burgess, S. J. et al. A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum . J. Med. Chem. 49, 5623–5625 (2006)

    Article  CAS  Google Scholar 

  28. Smilkstein, M., Sriwilaijaroen, N., Kelly, J. X., Wilairat, P. & Riscoe, M. Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob. Agents Chemother. 48, 1803–1806 (2004)

    Article  CAS  Google Scholar 

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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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Correspondence to Jane X. Kelly or Michael K. Riscoe.

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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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