title: Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrids.
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 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.
authors: Pharmaceutical Chemistry, North-West University, Potchefstroom 2531, South Africa.
authors: Marli C
authors: MC
authors: Lombard
authors: David D
authors: DD
authors: N'Da
authors: Christophe
authors: C
authors: Tran Van Ba
authors: Sharon
authors: S
authors: Wein
authors: Jennifer
authors: J
authors: Norman
authors: Lubbe
authors: L
authors: Wiesner
authors: Henri
authors: H
authors: Vial
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010961:Plasmodium / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011804:Quinolines