Antiplasmodial activity and in vivo bio-distribution of chloroquine molecules released with a 4-(4-ethynylphenyl)-triazole moiety from organometallo-cobalamins

Rossier, Jeremie; Sovari, Sara Nasiri; Pavic, Aleksandar; Vojnovic, Sandra; Stringer, Tameryn; Bättig, Sarah; Smith, Gregory S.; Nikodinovic-Runic, Jasmina; Zobi, Fabio

doi:10.3390/molecules24122310

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Antiplasmodial activity and in vivo bio-distribution of chloroquine molecules released with a 4-(4-ethynylphenyl)-triazole moiety from organometallo-cobalamins

Rossier, Jeremie Department of Chemistry, University of Fribourg, Switzerland
Sovari, Sara Nasiri Department of Chemistry, University of Fribourg, Switzerland
Pavic, Aleksandar Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Republic of Serbia
Vojnovic, Sandra Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Republic of Serbia
Stringer, Tameryn Department of Chemistry, University of Cape Town, Rondebosch, South Africa
Bättig, Sarah Department of Chemistry, University of Fribourg, Switzerland
Smith, Gregory S. Department of Chemistry, University of Cape Town, Rondebosch, South Africa
Nikodinovic-Runic, Jasmina Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Republic of Serbia
Zobi, Fabio Department of Chemistry, University of Fribourg, Switzerland

21.06.2019

Published in:

Molecules. - 2019, vol. 24, no. 12, p. 2310

English 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.

Faculty

Faculté des sciences et de médecine

Department

Département de Chimie

Language