title: Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model.
abstract: BACKGROUND
  Even though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. According to the World Malaria Report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. Thus, the discovery and development of new, effective anti-malarial drugs are required. To achieve this goal, the Department of Chemistry at the University of the Free State has synthesized a number of novel amino-alkylated chalcones and analogues, which showed in vitro anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. The lead compound (NP046) was selected for a comprehensive pharmacokinetic (PK) and in vivo efficacy evaluation in a mouse model.
  
  
  METHODS
  In vivo efficacy: Water solutions of NP046 were administered orally at 50 and 10 mg/kg using oral gavage and IV at 5 and 1 mg/kg via the dorsal penile vein to Plasmodium berghei (ANKA strain) infected male C57BL/6 mice (n = 5), once a day for four days. Blood samples were collected via tail bleeding in tubes containing phosphate buffer saline (PBS) on day five to determine the % parasitaemia by flow cytometry.In vivo PK: NP046 solutions in water were administered orally (50 and 10 mg/kg) and IV (5 mg/kg) to male C57BL/6 mice (n = 5). Blood samples were collected via tail bleeding into heparinized tubes and analysed using a validated LC-MS/MS assay. Data obtained from the concentration-time profile was evaluated using Summit PK software to determine the PK parameters of NP046.
  
  
  RESULTS
  NP046 inhibited parasite growth for the oral and IV groups. Better parasite growth inhibition was observed for the IV group. The PK evaluation of NP046 showed low oral bioavailability (3.2% and 6% at 50 mg/kg and 10 mg/kg dose, respectively and a moderate mean half-life ranging from 3.1 to 4.4 hours.
  
  
  CONCLUSIONS
  Even though the oral bioavailability of NP046 is low, its percentage parasite growth inhibition is promising, but in order to improve the oral bioavailability, structure-activity-relationship (SAR) optimization studies are currently being conducted.
authors.forename: Efrem T
authors.initials: ET
authors.lastname: Abay
authors.forename: Jan H
authors.initials: JH
authors.lastname: van der Westuizen
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Swart
authors.forename: Liezl
authors.initials: L
authors.lastname: Gibhard
authors.forename: Nina
authors.initials: N
authors.lastname: Lawrence
authors.forename: Ntokozo
authors.initials: N
authors.lastname: Dambuza
authors.forename: Anke
authors.initials: A
authors.lastname: Wilhelm
authors.forename: Kendrekar
authors.initials: K
authors.lastname: Pravin
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Observatory 7925, Cape Town, South Africa. lubbe.wiesner@uct.ac.za.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001769:Blood / Q000469:parasitology; D001774:Blood Chemical Analysis; D002853:Chromatography, Liquid; D004353:Drug Evaluation, Preclinical; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D010962:Plasmodium berghei / Q000302:isolation & purification; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials