1. Portland Veterans Affairs Medical Centre, Portland, Oregon 97239, USA
2. Department of Chemistry, Portland State University, Portland, Oregon 97201, USA
3. Oregon Health and Science University, Portland, Oregon 97239, USA
4. Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland
5. Department of Biological Sciences, Old Dominion University, Norfolk, Virginia 23529, USA
6. Present addresses: Oregon Translational Research and Drug Development Institute, Portland, Oregon 97201, USA (M.J.S.); Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia 23298, USA (K.D.L.).

Correspondence to: Jane X. Kelly^1,2Michael K. Riscoe^1,2,3 Correspondence and requests for materials should be addressed to J.X.K. (Email: kellyja@ohsu.edu) or M.K.R. (Email: riscoem@ohsu.edu).

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^{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 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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