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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

O'Neill, Paul M., Shone, Alison, Stanford, Deborah, Nixon, Gemma, Asadollahy, Eghbaleh, Park, B. Kevin, Maggs, James L., Roberts, Phil, Stocks, Paul A., Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Bray, Patrick, 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 and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2009) '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, Vol 52, Issue 7, pp. 1828-1844.

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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.

Item Type: Article
Additional Information: doi: 10.1021/jm8012757
Subjects: WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
QV Pharmacology > QV 38 Drug action.
QV Pharmacology > QV 34 Experimental pharmacology (General)
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1021/jm8012757
Depositing User: Mary Creegan
Date Deposited: 18 Jun 2010 15:27
Last Modified: 06 Feb 2018 12:59
URI: http://archive.lstmed.ac.uk/id/eprint/357

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