Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4′-fluoro and 4′-chloro analogues of amodiaquine. Identification of a suitable “ …

PM O'Neill, AE Shone, D Stanford…

Index: O'Neill, Paul M.; Shone, Alison E.; Stanford, Deborah; Nixon, Gemma; Asadollahy, Eghbaleh; Park, B. Kevin; Maggs, James L.; Roberts, Phil; Stocks, Paul A.; Biagini, Giancarlo; Bray, Patrick G.; Davies, Jill; Berry, Neil; Hall, Charlotte; Rimmer, Karen; Winstanley, Peter A.; Hindley, Stephen; Bambal, Ramesh B.; Davis, Charles B.; Bates, Martin; Gresham, Stephanie L.; Brigandi, Richard A.; Gomez-de-las-Heras, Federico M.; Gargallo, Domingo V.; Parapini, Silvia; Vivas, Livia; Lander, Hollie; Taramelli, Donatella; Ward, Stephen A. Journal of Medicinal Chemistry, 2009 , vol. 52, # 7 p. 1828 - 1844

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Citation Number: 37

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 ...