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Discovery Of Dual Function Acridones As A New Antimalarial Chemotype, Jane X. Kelly, 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
Discovery Of Dual Function Acridones As A New Antimalarial Chemotype, Jane X. Kelly, 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
Roland A. Cooper
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 …