PUBLICATION
Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins
- Authors
- Rossier, J., Nasiri Sovari, S., Pavic, A., Vojnovic, S., Stringer, T., Bättig, S., Smith, G.S., Nikodinovic-Runic, J., Zobi, F.
- ID
- ZDB-PUB-190627-1
- Date
- 2019
- Source
- Molecules 24(12): (Journal)
- Registered Authors
- Keywords
- antimalarial, chloroquine, cobalamin, in vivo, prodrug, triazole, zebrafish model
- MeSH Terms
-
- Antimalarials/chemistry
- Antimalarials/pharmacology
- Chloroquine/chemistry
- Chloroquine/pharmacology*
- Drug Resistance/drug effects
- Humans
- Malaria, Falciparum/drug therapy*
- Malaria, Falciparum/parasitology
- Molecular Structure
- Organometallic Compounds/chemistry
- Organometallic Compounds/pharmacology*
- Plasmodium falciparum/drug effects*
- Plasmodium falciparum/pathogenicity
- Triazoles/chemistry
- Vitamin B 12/chemistry
- PubMed
- 31234469 Full text @ Molecules
Citation
Rossier, J., Nasiri Sovari, S., Pavic, A., Vojnovic, S., Stringer, T., Bättig, S., Smith, G.S., Nikodinovic-Runic, J., Zobi, F. (2019) Antiplasmodial Activity and In Vivo Bio-Distribution of Chloroquine Molecules Released with a 4-(4-Ethynylphenyl)-Triazole Moiety from Organometallo-Cobalamins. Molecules. 24(12).
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping