The Quest of the Best – A SAR Study of Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds Presenting Antiparasitic Properties

Păunescu, Emilia; Boubaker, Ghalia; Desiatkina, Oksana; Anghel, Nicoleta; Amdouni, Yosra; Hemphill, Andrew; Furrer, Julien (2021). The Quest of the Best – A SAR Study of Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds Presenting Antiparasitic Properties. European journal of medicinal chemistry, 222, p. 113610. Elsevier Masson SAS 10.1016/j.ejmech.2021.113610

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A structure activity relationship (SAR) study of a library of 56 compounds (54 ruthenium and 2 osmium derivatives) based on the trithiolato-bridged dinuclear ruthenium(II)-arene scaffold (general formula [(η6-arene)2Ru2(μ2-SR)3]+, symmetric and [(η6-arene)2Ru2(μ2-SR1)2(μ2-SR2)]+, mixed, respectively) is reported. The 56 compounds (of which 34 are newly designed drug candidates) were synthesized by introducing chemical modifications at the level of bridge thiols, and they were grouped into eight families according to their structural features. The selected fittings were guided by previous results and focused on a fine-tuning of the physico-chemical and steric properties. Newly synthesized complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis, and four single-crystal X-ray structures were obtained. The in vitro biological assessment of the compounds was realized by applying a three-step screening cascade: (i) evaluation of the activity against Toxoplasma gondii RH strain tachyzoites expressing β-galactosidase (T. gondii-β-gal) grown in human foreskin fibroblast monolayers (HFF) and assessment of toxicity in non-infected HFF host cells; (ii) dose-response assays using selected compound, and (iii) studies on the effects in murine splenocytes. A primary screening was performed at 1 and 0.1 μM, and resulted in the selection of 39 compounds that inhibited parasite proliferation at 1 μM by more than 95% and reduced the viability of HFF by less than 49%. In the secondary screening, dose-response assays showed that the selected compounds exhibited half maximal inhibitory concentration (IC50) values for T. gondii-β-gal between 0.01 μM and 0.45 μM, with 30 compounds displaying an IC50 lower than 0.1 μM. When applied to non-infected HFF monolayers at 2.5 μM, 8 compounds caused more than 90% and 31 compounds more than 30% viability impairment. The tertiary screening included 14 compounds that did not cause HFF viability loss higher than 50% at 2.5 μM. These derivatives were assessed for potential immunosuppressive activities. First, splenocyte viability was assessed after treatment of cells with concanavalin A (ConA) and lipopolysaccharide (LPS) with compounds applied at 0.1 and 0.5 μM. Subsequently, the 5 compounds exhibiting the lowest splenocyte toxicity were further evaluated for their potential to inhibit B and T cell proliferation. Overall, compound 55 [(η6-p-MeC6H4Pri)2Ru2(μ2-SC6H4-o-CF3)2(μ2-SC6H4-p-OH)]Cl exhibited the most favorable features, and will be investigated as a scaffold for further optimization in terms of anti-parasitic efficacy and drug-like properties

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