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 E;
Stanford, Deborah;
Nixon, Gemma;
Asadollahy, Eghbaleh;
Park, B Kevin;
Maggs, James L;
Roberts, Phil;
Stocks, Paul A;
Biagini, Giancarlo;
+19 more...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;
(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, 52 (7).
pp. 1828-1844.
ISSN 0022-2623
DOI: https://doi.org/10.1021/jm8012757
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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.