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Isoquine and related amodiaquine analogues: A new generation of improved 4-aminoquinoline antimalarials

O'Neill, Paul M., Mukhtar, Amira, Stocks, Paul A., Randle, Laura E., Hindley, Stephen, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192, Storr, Richard C., Bickley, Jamie F., O'Neil, Ian A., Maggs, James L., Hughes, Ruth, Winstanley, Peter A., Bray, Patrick and Park, B. Kevin (2003) 'Isoquine and related amodiaquine analogues: A new generation of improved 4-aminoquinoline antimalarials'. Journal of Medicinal Chemistry, Vol 46, Issue 23, pp. 4933-4945.

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Abstract

Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3' hydroxyl and the 4' Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM +/- 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.

Item Type: Article
Additional Information: <Go to ISI>://WOS:000186347400016
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1021/jm030796n
Depositing User: Ms Julia Martin
Date Deposited: 18 Jun 2012 11:30
Last Modified: 17 Jul 2020 10:59
URI: https://archive.lstmed.ac.uk/id/eprint/2640

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