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.

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 / P.M. O'Neill, A.E. Shone, D. Stanford, G. Nixon, E. Asadollahy, B.K. Park, J.L. Maggs, P. Roberts, P.A. Stocks, G. Biagini, P.G. Bray, J. Davies, N. Berry, C. Hall, K. Rimmer, P.A. Winstanley, S. Hindley, R.B. Bambal, C.B. Davis, M. Bates, S.L. Gresham, R.A. Brigandi, F.M. Gomez-de-Las-Heras, D.V. Gargallo, S. Parapini, L. Vivas, H. Lander, D. Taramelli, S.A. Ward. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:7(2009 Apr 09), pp. 1828-1844.

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

S. Parapini;D. Taramelli
Penultimo
;
2009

Abstract

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.
Settore MED/04 - Patologia Generale
Settore MED/07 - Microbiologia e Microbiologia Clinica
9-apr-2009
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/58291
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