title: Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes.
abstract: BACKGROUND
  The use of amodiaquine in prophylaxis is associated with serious toxicity, resulting from its metabolic conversion into a reactive quinone-imine metabolite by the hepatic cytochrome P450. To circumvent this toxicity, several amodiaquine analogues that lack the potential to form a quinone-imine derivative, while retaining antimalarial activity, have been designed. Isoquine is one of these promising molecules that has already reached Phase I clinical trials in humans.
  
  
  METHODS
  We analysed the in vitro activity of isoquine against 62 Plasmodium falciparum isolates collected in Kenya and the association of this activity with polymorphisms in pfcrt and pfmdr1 genes.
  
  
  RESULTS
  The median concentration of isoquine that inhibited 50% of parasite growth (IC50) was 9 nM, compared with 56 nM chloroquine, 8 nM amodiaquine, 10 nM desethylamodiaquine, 69 nM lumefantrine and 1 nM dihydroartemisinin. Isoquine activity was correlated with polymorphisms in pfcrt at codon 76, but not in pfmdr1 at codon 86.
  
  
  CONCLUSIONS
  The high activity of isoquine against field isolates, including chloroquine-resistant isolates, with IC50 <10 nM, warrants its further development as an antimalarial.
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, PO Box 230, 80108 Kilifi, Kenya. jokombo@kemri-wellcome.org
authors.forename: John
authors.initials: J
authors.lastname: Okombo
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kiara
authors.forename: Abdi
authors.initials: A
authors.lastname: Abdirahman
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.forename: Eric
authors.initials: E
authors.lastname: Ohuma
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.forename: Steve
authors.initials: S
authors.lastname: Ward
mesh_terms: D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007630:Kenya; D016778:Malaria, Falciparum / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics*
chemical_list: D000655:Amodiaquine; D000962:Antimalarials; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum