Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins
Jeremie Rossier,
Sara Nasiri Sovari,
Aleksandar Pavic,
Sandra Vojnovic,
Tameryn Stringer,
Sarah Bättig,
Gregory S. Smith,
Jasmina Nikodinovic-Runic,
Fabio Zobi
Affiliations
Jeremie Rossier
Department of Chemistry, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
Sara Nasiri Sovari
Department of Chemistry, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
Aleksandar Pavic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Republic of Serbia
Sandra Vojnovic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Republic of Serbia
Tameryn Stringer
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Sarah Bättig
Department of Chemistry, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
Gregory S. Smith
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Jasmina Nikodinovic-Runic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Republic of Serbia
Fabio Zobi
Department of Chemistry, University of Fribourg, Chemin du Musée 10, 1700 Fribourg, Switzerland
We have explored the possibility of using organometallic derivatives of cobalamin as a scaffold for the delivery of the same antimalarial drug to both erythro- and hepatocytes. This hybrid molecule approach, intended as a possible tool for the development of multi-stage antimalarial agents, pivots on the preparation of azide-functionalized drugs which, after coupling to the vitamin, are released with a 4-(4-ethynylphenyl)-triazole functionality. Three chloroquine and one imidazolopiperazine derivative (based on the KAF156 structure) were selected as model drugs. One hybrid chloroquine conjugate was extensively studied via fluorescent labelling for in vitro and in vivo bio-distribution studies and gave proof-of-concept for the design. It showed no toxicity in vivo (zebrafish model) as well as no hepatotoxicity, no cardiotoxicity or developmental toxicity of the embryos. All 4-(4-ethynylphenyl)-triazole derivatives of chloroquine were equally active against chloroquine-resistant (CQR) and chloroquine-sensitive (CQS) Plasmodium falciparum strains.
