| Summary: | The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic <i>Toxoplasma</i><i>gondii</i> tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited <i>T.</i><i>gondii</i> proliferation with IC<sub>50</sub> values ranging from 90 to 539 nM, and seven derivatives displayed IC<sub>50</sub> values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-<i>Toxoplasma</i> activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC<sub>50</sub> values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC<sub>50</sub> values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates <b>6</b>–<b>10</b> and <b>20</b> exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues <b>11</b>–<b>14</b>, <b>23,</b> and <b>24</b>. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.
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