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.
|Titolo:||Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine : identification of a suitable "back-up" compound for N-tert-butyl isoquine|
TARAMELLI, DONATELLA (Penultimo)
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/07 - Microbiologia e Microbiologia Clinica
|Data di pubblicazione:||9-apr-2009|
|Digital Object Identifier (DOI):||10.1021/jm8012757|
|Appare nelle tipologie:||01 - Articolo su periodico|