Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 7, Pages 1828-1844Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8012757
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- EU
- Medical Research Council [G0700654B] Funding Source: researchfish
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On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline arnodiaquine (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.
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