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Open Access Research

Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids

Marli C Lombard1, David D N’Da1*, Christophe Tran Van Ba2, Sharon Wein2, Jennifer Norman3, Lubbe Wiesner3 and Henri Vial2

Author Affiliations

1 Pharmaceutical Chemistry, North-West University, Potchefstroom 2531, South Africa

2 Centre National de la Recherche Scientifique, Université Montpellier 2, 34095, Montpellier Cedex 05, France

3 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town 7925, South Africa

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Malaria Journal 2013, 12:71  doi:10.1186/1475-2875-12-71

Published: 21 February 2013

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 0.8 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 13 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.

Keywords:
Malaria; Artemisinin; Quinoline; Hybrid; Pharmacokinetics; In vivo activity