title: A primaquine-chloroquine hybrid with dual activity against Plasmodium liver and blood stages.
abstract: We present a new class of hybrid molecules consisting of the established antiplasmodial drugs primaquine and chloroquine. No drug is known to date that acts comparably against all stages of Plasmodium in its life cycle. Starting from available precursors, we designed and synthesized a new-generation compound consisting of both primaquine and chloroquine components, with the intent to produce agents that exhibit bioactivity against different stages of the parasite's life cycle. In vitro, the hybrid molecule 3 displays activity against both asexual and sexual P. falciparum blood stages as well as P. berghei sporozoites and liver stages. In vivo, the hybrid elicits activity against P. berghei liver and blood stages. Our results successfully validate the concept of utilizing one compound to combine different modes of action that attack different Plasmodium stages in the mammalian host. It is our hope that the novel design of such compounds will outwit the pathogen in the spread of drug resistance. Based on the optimized synthetic pathway, the compound is accessible in a smooth and versatile way and open for potential further molecular modification.
authors.affiliation: Institute of Organic Chemistry, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Lödige
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lewis
authors.forename: Eleonora S
authors.initials: ES
authors.lastname: Paulsen
authors.forename: Harald L
authors.initials: HL
authors.lastname: Esch
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.forename: Leane
authors.initials: L
authors.lastname: Lehmann
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mueller
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001769:Blood / Q000469:parasitology; D002678:Chimera; D002738:Chloroquine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011319:Primaquine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D002738:Chloroquine; D011319:Primaquine
keywords: Chloroquine; Hybrid molecules; Multistage; Plasmodium; Primaquine