Characterization of the Activities of Dinuclear Thiolato-Bridged Arene Ruthenium Complexes against Toxoplasma gondii [PublishAheadOfPrint]

The in vitro effects of 18 dinuclear-thiolato bridged arene ruthenium complexes, (1 mono-, 4 di- and 13-tri-thiolato compounds), originally designed as anti-cancer agents, were studied in the apicomplexan parasite Toxoplasma gondii grown in human foreskin fibroblast host cells (HFF). Some tri-thiolato compounds exhibited anti-parasitic efficacy at 250 nM and below. Among those, complex 1 and complex 2 inhibited T. gondii proliferation with IC₅₀ values of 34 and 62 nM, respectively, and they did not affect HFF at dosages of 200 μM or above, resulting in selectivity indices of > 23' 000. The IC₅₀ values of complex 9 were 1.2 nM for T. gondii and above 5 μM for HFF. TEM detected ultrastructural alterations in the matrix of the parasite mitochondria at the early stages of treatment, followed by more pronounced destruction of tachyzoites. However, all three compounds applied at 250 nM for 15 days were not parasiticidal. By affinity chromatography using complex 9 coupled to epoxy-activated sepharose followed by mass spectrometry, T. gondii translation elongation factor-1 alpha and two ribosomal proteins, RPS18, and RPL27 were identified as potential binding proteins. In conclusion, organometallic ruthenium complexes exhibit promising activities against Toxoplasma, and potential mechanisms of action of these compounds as well as their prospective applications for the treatment of toxoplasmosis are discussed.

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