Discovery of dual function acridones as a new antimalarial chemotype.
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.
Kelly
Jane X
JX
Portland Veterans Affairs Medical Centre, Portland, Oregon 97239, USA. kellyja@ohsu.edu
Smilkstein
Martin J
MJ
Brun
Reto
R
Wittlin
Sergio
S
Cooper
Roland A
RA
Lane
Kristin D
KD
Janowsky
Aaron
A
Johnson
Robert A
RA
Dodean
Rozalia A
RA
Winter
Rolf
R
Hinrichs
David J
DJ
Riscoe
Michael K
MK
D054831:Acridones / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D004351:Drug Resistance / Q000187:drug effects; D004357:Drug Synergism; D006418:Heme / Q000037:antagonists & inhibitors / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D010967:Plasmodium yoelii / Q000187:drug effects; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011803:Quinine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D053058:Trophozoites / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D010879:Piperazines
D054831:Acridones; D000962:Antimalarials; D006418:Heme; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D011803:Quinine; D011804:Quinolines; D014700:Verapamil; C416369:PfCRT protein, Plasmodium falciparum; C541650:chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)acridone; C034759:piperaquine; D010879:Piperazines; C037219:quinoline