title: Antiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse model.
abstract: BACKGROUND
  During the erythrocytic stage in humans, malaria parasites digest haemoglobin of the host cell, and the toxic haem moiety crystallizes into haemozoin. Chloroquine acts by forming toxic complexes with haem molecules and interfering with their crystallization. In chloroquine-resistant strains, the drug is excluded from the site of action, which causes the parasites to accumulate less chloroquine in their acid food vacuoles than chloroquine-sensitive parasites. 3-Hydroxylpyridin-4-ones are known to chelate iron; hydroxypyridone-chloroquine (HPO-CQ) hybrids were synthesized in order to determine whether they can inhibit parasites proliferation in the parasitic digestive vacuole by withholding iron from plasmodial parasite metabolic pathway.
  
  
  METHODS
  Two HPO-CQ hybrids were tested against Plasmodium falciparum chloroquine-sensitive (D10 and 3D7) and -resistant strains (Dd2 and K1). The pharmacokinetic properties of active compounds were determined using a mouse model and blood samples were collected at different time intervals and analysed using LC-MS/MS. For in vivo efficacy the mice were infected with Plasmodium berghei in a 4-day Peters' test. The parasitaemia was determined from day 3 and the course of the infection was followed by microscopic examination of stained blood films every 2-3 days until a rise in parasitaemia was observed in all test subjects.
  
  
  RESULTS
  IC50 values of the two compounds for sensitive and resistant strains were 0.064 and 0.047 µM (compound 1), 0.041 and 0.122 µM (compound 2) and 0.505 and 0.463 µM (compound 1), 0.089 and 0.076 µM (compound 2), respectively. Pharmacokinetic evaluation of these compounds showed low oral bioavailability and this affected in vivo efficacy when compounds were dosed orally. However, when dosed intravenously compound 1 showed a clearance rate of 28 ml/min/kg, an apparent volume of distribution of 20 l/kg and a half-life of 4.3 h. A reduction in parasitaemia was observed when compound 1 was dosed intravenously for four consecutive days in P. berghei-infected mice. However, a rise in parasitaemia levels was observed on day 6 and on day 9 for chloroquine-treated mice.
  
  
  CONCLUSIONS
  The hybrid compounds that were tested were able to reduce parasitaemia levels in P. berghei-infected mice when dosed intravenously, but parasites recrudesced 24 h after the administration of the least dose. Despite low oral bioavailability, the IV data obtained suggests that further structural modifications may lead to the identification of more HPO-CQ hybrids with improved pharmacokinetic properties and in vivo efficacy.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa. ntokozo.dambuza@telkomsa.net.
authors.forename: Ntokozo S
authors.initials: NS
authors.lastname: Dambuza
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa. peter.smith@uct.ac.za.
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa. alicia.evans@uct.ac.za.
authors.forename: Alicia
authors.initials: A
authors.lastname: Evans
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa. jennifer.norman@uct.ac.za.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Norman
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa. dale.taylor@uct.ac.za.
authors.forename: Dale
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa. andrewandayi@yahoo.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Andayi
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa. timothy.egan@uct.ac.za.
authors.forename: Timothy
authors.initials: T
authors.lastname: Egan
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa. kelly.chibale@uct.ac.za.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa. lubbe.wiesner@uct.ac.za.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001774:Blood Chemical Analysis; D002738:Chloroquine / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011728:Pyridones / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D011728:Pyridones; D002738:Chloroquine