Investigation of bioorganometallic artemisinins as antiplasmodials

Abstract

The aim of this study was to improve the activity of artemisinin-based compounds for the treatment of malaria, primarily caused by Plasmodium falciparum. The artemisinin scaffold was functionalized with an appropriate N,N’– coordinated ruthenium p-cymene complex or ferrocene complex. For the preparation of the ruthenium complexes, two novel ligands were prepared: artemisinyl-triazole pyridine (compound 1) and pyridyl amido-artesunate (compound 4). The organometallic moieties were linked by a triazole or an amide-alkyl-ester to the artemisinin scaffold. Six new organometallic artemisinin-based complexes were synthesised and characterised (compounds 2a, 2b, 3, 5a, 5b and 6). Of the six organometallic artemisinin compounds, the ferrocenyl amido-artesunate, compound 6, was the most active against the chloroquine-resistant strain (Dd2) with IC50 = 3.0 nM ± 1.6 nM followed by the triazole derivative, compound 3, with IC50 = 4.8 nM ± 0.6 nM. The most active compound overall was the ligand precursor, compound 4 with IC50 = 0.6 nM ± 0.1 nM. All compounds showed almost no cytotoxicity towards the HEK293 cell line. The “most” cytotoxic agent was compound 1, with IC50 = 5975.0 nM ± 912 nM, which is 1810-fold higher compared to its activity against the Dd2 strain.