Trithiolato-Bridged Dinuclear Arene Ruthenium(ll)- Glycoconjugates: Synthesis and Antiparasitic Activity

Eight novel carbohydrate-tethered trithiolato dinuclear ruthenium(II)-arene complexes were synthesized using CuAAC 'click' (Cu(I)-catalyzed azide-alkyne cycloaddition) reactions and, together with the diruthenium intermediates, were assessed for their in vitro activity against transgenic Toxoplasma gondii (T. gondii) tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal), and for their cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFFs). The results revealed that the biological activity of the hybrids was influenced by both the nature of the carbohydrate (glucose or galactose) attached to the ruthenium complex and the type/length of the linker between the two units. For seven selected diruthenium-carbohydrate conjugates, the values of the half-maximal inhibitory concentration (IC50) on T. gondii β-gal and HFFs viability for a compound concentration of 2.5 μM were measured. Remarkably, two galactose-diruthenium conjugates, 23 and 26, performed significantly better than the corresponding unlabeled diruthenium complexes and the standard drug Pyrimethamine, with very low IC50 values (23: IC50 = 0.032 μM, 26: IC50 = 0.153 μM, Pyrimethamine, IC50 = 0.326 μM) and a very low toxicity on HFFs (viability 92% for 23 and 97% for 26). Overall, our study shows that conjugation of carbohydrates to diruthenium compounds is a promising approach to develop new effective antiparasitic compounds with reduced toxicity.