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Discovery of dual function acridones as a new antimalarial chemotype

Kelly, J. X. and Smilkstein, M. J. and Brun, R. and Wittlin, S. and Cooper, R. A. and Lane, K. D. and Janowsky, A. and Johnson, R. A. and Dodean, R. A. and Winter, R. and Hinrichs, D. J. and Riscoe, M. K.. (2009) Discovery of dual function acridones as a new antimalarial chemotype. Nature, Vol. 459, H. 7244. S. 270-273.

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Official URL: http://edoc.unibas.ch/dok/A5843189

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Wittlin, Sergio
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Macmillan
ISSN:0028-0836
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:29 Jan 2016 07:59
Deposited On:14 Sep 2012 06:39

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