New Nucleic Base-Tethered Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity.

Aiming toward compounds with improved anti- activity by exploiting the parasite auxotrophies, a library of nucleobase-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates was synthesized and evaluated. Structural features such as the type of nucleobase and linking unit were progressively modified. For comparison, diruthenium hybrids with other type of molecules were also synthesized and assessed. A total of 37 compounds (diruthenium conjugates and intermediates) were evaluated in a primary screening for in vitro activity against transgenic tachyzoites constitutively expressing β-galactosidase ( β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. Twenty compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to β-gal half maximal inhibitory concentration determination (IC) and their toxicity for HFF was assessed at 2.5 µM. Two promising compounds were identified: , ester conjugate with 9-(2-oxyethyl)adenine, and , a click conjugate bearing a 2-(4-(hydroxymethyl)-1-1,2,3-triazol-1-yl)methyl substituent, with IC values of 0.059 and 0.111 µM respectively, significantly lower compared to pyrimethamine standard (IC = 0.326 µM). Both and exhibited low toxicity against HFF when applied at 2.5 µM and are candidates for potential treatment options in a suitable in vivo model.