title: 3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine.
abstract: Chloroquine (CQ), the first cost-effective synthetic antimalarial, is rendered ineffective in malaria-endemic regions owing to the rise and spread of CQ-resistant Plasmodium falciparum. In this report, we show that a halogen derivative of CQ, namely 3-iodo-CQ, inhibits the proliferation of CQ-sensitive and -resistant P. falciparum in a verapamil-insensitive manner. Similar to CQ, the antimalarial activity of 3-iodo-CQ is likely due to its inhibition of β-haematin formation. Interestingly, the presence of non-inhibitory concentrations of 3-iodo-CQ potentiated the antiproliferative activity of CQ against CQ-resistant strains or P. falciparum transfectants expressing wild-type or mutant P. falciparum CQ resistance transporter (PfCRT) (C2(GC03) or C4(Dd2), respectively). These findings demonstrate that halogenation of the third position of 4-aminoquinoline, with a simple one-step reaction from CQ, generates a novel derivative that is active against CQ-sensitive and -resistant P. falciparum, possibly by inhibiting the activity of mutant PfCRT.
authors.affiliation: Institute of Parasitology, Macdonald Campus, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Edaye
authors.affiliation: Department of Chemistry, McGill University, Quebec, Canada.
authors.forename: Dagobert
authors.initials: D
authors.lastname: Tazoo
authors.affiliation: Department of Chemistry, McGill University, Quebec, Canada.
authors.forename: D Scott
authors.initials: DS
authors.lastname: Bohle
authors.affiliation: Institute of Parasitology, Macdonald Campus, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada. Electronic address: elias.georges@McGill.ca.
authors.forename: Elias
authors.initials: E
authors.lastname: Georges
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D054879:Halogenation; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D002738:Chloroquine; C001920:4-aminoquinoline
keywords: 3-Iodo-chloroquine; Malaria; PfCRT inhibitors