Abstract
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / pharmacokinetics
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Aminoquinolines / pharmacology
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Amodiaquine / analogs & derivatives*
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Amodiaquine / chemical synthesis*
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Amodiaquine / chemistry
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Amodiaquine / pharmacokinetics
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Amodiaquine / pharmacology
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / pharmacokinetics
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Antimalarials / pharmacology
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Cell Survival
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Chloroquine / pharmacology
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Dogs
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Drug Resistance
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Female
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Haplorhini
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Hepatocytes / cytology
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Hepatocytes / drug effects
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Humans
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In Vitro Techniques
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Malaria / drug therapy
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Malaria / parasitology
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Male
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Mice
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Parasitic Sensitivity Tests
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Plasmodium berghei / drug effects
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Plasmodium falciparum / drug effects
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Plasmodium yoelii / drug effects
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Rats
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Rats, Wistar
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Structure-Activity Relationship
Substances
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(3-(tert-butylaminomethyl)-4-fluorophenyl)(7-chloroquinolin-4-yl)amine
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Aminoquinolines
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Antimalarials
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N-tert-butylisoquine
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Amodiaquine
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Chloroquine