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ACS Med Chem Lett. 2013 Oct 1;4(12):1198-202. doi: 10.1021/ml400311r. eCollection 2013 Dec 12.

Synthesis and in vitro and in vivo pharmacological evaluation of new 4-aminoquinoline-based compounds.

Author information

1
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
2
Department of Chemistry (48), University of the Free State , Bloemfontein 339, South Africa ; PAREXEL International Clinical Research Organization , Private Bag X09, Brandhof 9324, Bloemfontein 339, South Africa.
3
Department of Pharmacology, University of Cape Town, Medical School , Observatory 7925, South Africa.
4
PAREXEL International Clinical Research Organization , Private Bag X09, Brandhof 9324, Bloemfontein 339, South Africa.
5
Department of Medicine, San Francisco General Hospital, University of San Francisco , San Francisco, California 94143, United States.
6
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , Basel CH-4057, Switzerland.
7
Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa ; Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.

Abstract

A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitro. Pharmacokinetic studies on 3d and 3e in mice showed that they had moderate half-life (4-6 h) and low oral bioavailability. The front runner compound 3d exhibited moderate inhibition of the malaria parasite on P. berghei infected mice following oral administration (5 mg/kg), achieving reduction of parasitemia population by 47% on day 7.

KEYWORDS:

Aminoquinolines; antiplasmodial activity; pharmacokinetics; plasma protein binding

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