New Nucleic Base-tethered Trithiolato-bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Aiming to generate novel compounds with improved antitoxoplama activity by exploiting the parasite auxotrophies, a library of nucleic base-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates - was synthesized and evaluated. Various structural features as the nucleobase (adenine, uracil, cytosine, thymine, and xanthine) and the linker between the two units were progressively modified. To substantiate the concept, hybrid molecules comprising the diruthenium moiety and other type of pendant molecules were also synthesized and assessed. The use of the CuAAC (copper catalyzed azide-alkyne cycloaddition) approach for the obtainment of conjugates bearing the trithiolato diruthenium scaffold was validated. 37 Compounds (diruthenium conjugates and corresponding intermediates) were assessed in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii 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. 20 Compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal dose-response studies (IC50, half maximal inhibitory concentration determination) and their toxicity for HFF was assessed at 2.5 μM. Two compounds showing promise for further development were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC50 values of 0.059 and 0.111 μM respectively, significantly lower compared to the standard drug pyrimethamine (IC50 = 0.326 μM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 μM and are candidates as potential treatment options in a suitable in vivo model.