Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids
Journal Article
2013
Permanent link to this Item
Authors
Journal Title
Malaria Journal
Link to Journal
Journal ISSN
Volume Title
Publisher
BioMed Central Ltd
Publisher
University of Cape Town
Department
Faculty
Series
Abstract
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 0.8mg/kg, 2.5mg/kg, 7.5mg/kg or 15mg/kg intraperitoneally (ip), or orally (per os) with 2.7mg/kg, 8.3mg/kg, 25mg/kg or 50mg/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 <0.8mg/kg by the ip route and 12, 16 and 13mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15mg/kg via ip route and at 50mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30mg/kg ip and 80mg/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.
Description
Reference:
Lombard, M. C., N’Da, D. D., Van Ba, C. T., Wein, S., Norman, J., Wiesner, L., & Vial, H. (2013). Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids. Malar J, 12, 71.