Trithiolato-bridged dinuclear ruthenium(II)-arene conjugates tethered with lipophilic units: Synthesis and Toxoplasma gondii antiparasitic activity

Abstract

Trithiolato-bridged dinuclear ruthenium(II)-arene complexes are active against various parasites including Toxoplasma gondii. Lipids, isoprenoids and lipoate are metabolites scavenged by T. gondii from the host cell but also synthesized by the parasite, and these molecules can be appended to the diruthenium moiety in a conjugate approach aiming at compounds with improved antiparasitic activity and selectivity. The synthesis and in vitro T. gondii activity evaluation of 23 new trithiolato diruthenium complexes bearing various lipophilic units are reported. The influence of several structural elements as the nature of the lipophilic pendant and the type of the connecting bond between the two units on the conjugates’ biological properties were examined. In a primary screening, the antiparasitic efficacy and cytotoxicity were assessed at 0.1 and 1 µM against transgenic T. gondii tachyzoites constitutively expressing β-galactosidase and on human foreskin fibroblasts (HFF) host cells. For 14 selected conjugates the half-maximal inhibitory concentration (IC50) on T. gondii and their effect on HFF viability at 2.5 µM were determined. The decanoic, oleic and elaidic ester conjugates 13a, 16a and 17a efficiently inhibited parasite proliferation (IC50 values of 0.065, 0.127 and 0.123 µM, respectively) with no effect on HFF viability at 2.5 µM and deserve further attention.