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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.


Paul M O'Neill, Alison E Shone, Deborah Stanford, Gemma Nixon, Eghbaleh Asadollahy, B Kevin Park, James L Maggs, Phil Roberts, Paul A Stocks, Giancarlo Biagini, Patrick G Bray, Jill Davies, Neil Berry, Charlotte Hall, Karen Rimmer, Peter A Winstanley, Stephen Hindley, Ramesh B Bambal, Charles B Davis, Martin Bates, Stephanie L Gresham, Richard A Brigandi, Federico M Gomez-de-Las-Heras, Domingo V Gargallo, Silvia Parapini, Livia Vivas, Hollie Lander, Donatella Taramelli, Stephen A Ward. 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. Journal of medicinal chemistry. 2009 Apr 9;52(7):1828-44

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PMID: 19284751

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