Synthesis And Antiparasitic Activity Of New Conjugates-Organic Drugs Tethered To Trithiolato-Bridged Dinuclear Ruthenium(Ii)-Arene Complexes

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)-arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4-naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing beta-galactosidase (T. gondii beta-gal) at 0.1 and 1 mu M. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 mu M, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii beta-gal dose-response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half-maximal inhibitory concentration) values 0.063 and 0.152 mu M, and low or intermediate impairment of HFF viability at 2.5 mu M (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity.