Lombard M.C., N'Da D.D., Tran Van Ba C., Wein S., Norman J., Wiesner L., Vial H.
Pharmaceutical Chemistry, North-West University, Potchefstroom 2531, South Africa; Centre National de la Recherche Scientifique, Université Montpellier 2, 34095, Montpellier Cedex 05, France; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town 7925, South Africa
Lombard, M.C., Pharmaceutical Chemistry, North-West University, Potchefstroom 2531, South Africa; N'Da, D.D., Pharmaceutical Chemistry, North-West University, Potchefstroom 2531, South Africa; Tran Van Ba, C., Centre National de la Recherche Scientifique, Université Montpellier 2, 34095, Montpellier Cedex 05, France; Wein, S., Centre National de la Recherche Scientifique, Université Montpellier 2, 34095, Montpellier Cedex 05, France; Norman, J., Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town 7925, South Africa; Wiesner, L., Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town 7925, South Africa; Vial, H., Centre National de la Recherche Scientifique, Université Montpellier 2, 34095, Montpellier Cedex 05, France
Background: Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. Methods. In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 - 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. Results: Hybrids 1 - 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os. Conclusions: These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated. © 2013 Lombard et al; licensee BioMed Central Ltd.
aminoquinoline derivative; antimalarial agent; artemisinin; artesunate; antimalarial activity; article; in vitro study; in vivo study; male; mouse; nonhuman; parasitemia; Plasmodium falciparum; Plasmodium vinckei; Plasmodium vinckei infection; Administration, Intravenous; Administration, Oral; Animals; Antimalarials; Artemisinins; Disease Models, Animal; Drug Combinations; Malaria; Mice; Parasitic Sensitivity Tests; Plasmodium; Quinolines; Treatment Outcome