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

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; Steve Ward

doi:10.1021/jm8012757

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

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 BatesStephanie L. Gresham, Richard A. Brigandi, Federico M. Gomez-de-las-Heras, Domingo V. Gargallo, Silvia Parapini, Livia Vivas, Hollie Lander, Donatella Taramelli, Steve Ward

Tropical Disease Biology

Research output: Contribution to journal › Article › peer-review

61 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1828-1844
Number of pages	17
Journal	Journal of Medicinal Chemistry
Volume	52
Issue number	7
DOIs	https://doi.org/10.1021/jm8012757
Publication status	Published - 9 Apr 2009

Access to Document

10.1021/jm8012757

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this

O'Neill, P. M., Shone, A. E., Stanford, D., Nixon, G., Asadollahy, E., Park, B. K., Maggs, J. L., Roberts, P., Stocks, P. A., Biagini, G., Bray, P. G., Davies, J., Berry, N., Hall, C., Rimmer, K., Winstanley, P. A., Hindley, S., Bambal, R. B., Davis, C. B., ... Ward, S. (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), 1828-1844. https://doi.org/10.1021/jm8012757

@article{7458a4ef24fb48e1a0df2e08bb2a15ec,

title = "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",

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.",

author = "O'Neill, \{Paul M.\} and Shone, \{Alison E.\} and Deborah Stanford and Gemma Nixon and Eghbaleh Asadollahy and Park, \{B. Kevin\} and Maggs, \{James L.\} and Phil Roberts and Stocks, \{Paul A.\} and Giancarlo Biagini and Bray, \{Patrick G.\} and Jill Davies and Neil Berry and Charlotte Hall and Karen Rimmer and Winstanley, \{Peter A.\} and Stephen Hindley and Bambal, \{Ramesh B.\} and Davis, \{Charles B.\} and Martin Bates and Gresham, \{Stephanie L.\} and Brigandi, \{Richard A.\} and Gomez-de-las-Heras, \{Federico M.\} and Gargallo, \{Domingo V.\} and Silvia Parapini and Livia Vivas and Hollie Lander and Donatella Taramelli and Steve Ward",

year = "2009",

month = apr,

day = "9",

doi = "10.1021/jm8012757",

language = "English",

volume = "52",

pages = "1828--1844",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "7",

}

O'Neill, PM, Shone, AE, Stanford, D, Nixon, G, Asadollahy, E, Park, BK, Maggs, JL, Roberts, P, Stocks, PA, Biagini, G, Bray, PG, Davies, J, Berry, N, Hall, C, Rimmer, K, Winstanley, PA, Hindley, S, Bambal, RB, Davis, CB, Bates, M, Gresham, SL, Brigandi, RA, Gomez-de-las-Heras, FM, Gargallo, DV, Parapini, S, Vivas, L, Lander, H, Taramelli, D & Ward, S 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, no. 7, pp. 1828-1844. https://doi.org/10.1021/jm8012757

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 et al.
In: Journal of Medicinal Chemistry, Vol. 52, No. 7, 09.04.2009, p. 1828-1844.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - O'Neill, Paul M.

AU - Shone, Alison E.

AU - Stanford, Deborah

AU - Nixon, Gemma

AU - Asadollahy, Eghbaleh

AU - Park, B. Kevin

AU - Maggs, James L.

AU - Roberts, Phil

AU - Stocks, Paul A.

AU - Biagini, Giancarlo

AU - Bray, Patrick G.

AU - Davies, Jill

AU - Berry, Neil

AU - Hall, Charlotte

AU - Rimmer, Karen

AU - Winstanley, Peter A.

AU - Hindley, Stephen

AU - Bambal, Ramesh B.

AU - Davis, Charles B.

AU - Bates, Martin

AU - Gresham, Stephanie L.

AU - Brigandi, Richard A.

AU - Gomez-de-las-Heras, Federico M.

AU - Gargallo, Domingo V.

AU - Parapini, Silvia

AU - Vivas, Livia

AU - Lander, Hollie

AU - Taramelli, Donatella

AU - Ward, Steve

PY - 2009/4/9

Y1 - 2009/4/9

N2 - 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.

AB - 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.

U2 - 10.1021/jm8012757

DO - 10.1021/jm8012757

M3 - Article

SN - 0022-2623

VL - 52

SP - 1828

EP - 1844

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 7

ER -

O'Neill PM, Shone AE, Stanford D, Nixon G, Asadollahy E, Park BK et al. 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):1828-1844. doi: 10.1021/jm8012757