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A primaquine-chloroquine hybrid with dual activity against Plasmodium liver and blood stages

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...

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Hauptverfasser: Loedige, Melanie (VerfasserIn) , Lewis, Matthew (VerfasserIn) , Paulsen, Eleonora S. (VerfasserIn) , Esch, Harald L. (VerfasserIn) , Pradel, Gabriele (VerfasserIn) , Lehmann, Leane (VerfasserIn) , Brun, Reto (VerfasserIn) , Bringmann, Gerhard (VerfasserIn) , Müller, Ann-Kristin (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 5 August 2013
In: International journal of medical microbiology
Year: 2013, Jahrgang: 303, Heft: 8, Pages: 539-547
ISSN:1618-0607
DOI:10.1016/j.ijmm.2013.07.005
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ijmm.2013.07.005
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S143842211300101X
Volltext
Verfasserangaben:Melanie Lödige, Matthew D. Lewis, Eleonora S. Paulsen, Harald L. Esch, Gabriele Pradel, Leane Lehmann, Reto Brun, Gerhard Bringmann, Ann-Kristin Mueller
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 19.05.2021
Beschreibung:Online Resource
ISSN:1618-0607
DOI:10.1016/j.ijmm.2013.07.005

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