Abstract
A class of hybrid molecules which we term 'reversed chloroquines' (RCQs) was designed, and a prototype molecule, N'-(7-chloroquinolin-4-yl)-N-[3-(10,11-dihydrodibenzo[b,f]azepin-5-yl)propyl]-N-methylpropane-1,3-diamine (1), was synthesized and tested against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. An in vitro assay against the two strains indicated that 1 was effective at low-nM concentrations against both strains. A preliminary study in mice demonstrated oral efficacy against P. chabaudi and the absence of obvious toxicity. The RCQ approach therefore appears to be feasible.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology*
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Chloroquine / analogs & derivatives*
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Chloroquine / chemical synthesis
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Chloroquine / chemistry
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Chloroquine / pharmacology*
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Dibenzazepines / chemical synthesis*
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Dibenzazepines / chemistry
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Dibenzazepines / pharmacology
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Drug Resistance*
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Female
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Malaria / drug therapy
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Malaria / parasitology
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Mice
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Plasmodium chabaudi
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Plasmodium falciparum / drug effects*
Substances
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Antimalarials
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Dibenzazepines
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N'-(7-chloroquinolin-4-yl)-N-(3-(10,11-dihydrodibenzo(b,f)azepin-5-yl)propyl)-N-methylpropane-1,3-diamine
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Chloroquine