title: Synthesis and in vitro and in vivo pharmacological evaluation of new 4-aminoquinoline-based compounds.
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.
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Matshawandile
authors.initials: M
authors.lastname: Tukulula
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Mathew
authors.initials: M
authors.lastname: Njoroge
authors.affiliation: 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.
authors.forename: Efrem T
authors.initials: ET
authors.lastname: Abay
authors.affiliation: Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
authors.forename: Grace C
authors.initials: GC
authors.lastname: Mugumbate
authors.affiliation: Department of Pharmacology, University of Cape Town, Medical School , Observatory 7925, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Department of Pharmacology, University of Cape Town, Medical School , Observatory 7925, South Africa.
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology, University of Cape Town, Medical School , Observatory 7925, South Africa.
authors.forename: Liezl
authors.initials: L
authors.lastname: Gibhard
authors.affiliation: Department of Pharmacology, University of Cape Town, Medical School , Observatory 7925, South Africa.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Norman
authors.affiliation: PAREXEL International Clinical Research Organization , Private Bag X09, Brandhof 9324, Bloemfontein 339, South Africa.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Swart
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of San Francisco , San Francisco, California 94143, United States.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Department of Medicine, San Francisco General Hospital, University of San Francisco , San Francisco, California 94143, United States.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , Basel CH-4057, Switzerland.
authors.forename: Samuel
authors.initials: S
authors.lastname: Barteau
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , Basel CH-4057, Switzerland.
authors.forename: Judith
authors.initials: J
authors.lastname: Streckfuss
authors.affiliation: Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research , Basel CH-4057, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Kameni-Tcheudji
authors.affiliation: 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.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
keywords: Aminoquinolines; antiplasmodial activity; pharmacokinetics; plasma protein binding