Ruthenium(II)–arene complexes with chelating quinoline ligands as anti-amyloid agents

Recent recognition of the soluble form of the amyloid-beta (Aβ) peptide as a neurotoxic agent in Alzheimer’s disease (AD) has spurred the development of agents to target this species. Because Aβ is known to chelate metal ions in solution, metal-based therapeutics are uniquely suited to exploit this affinity, where coordination to Aβ has been shown to impact the neurotoxicity of the peptide. Ruthenium(II)–arene complexes are unique candidates for evaluation, as one face of the molecule is blocked by the hydrophobic arene ring, while coordination to the Aβ peptide can occur on the other side of the molecule. We have prepared and evaluated two Ru(II)–arene complexes with chelating quinoline-based ligands, Ru1 and Ru2, for their respective anti-amyloid abilities. Although both complexes decreased the aggregation of soluble Aβ, Ru1 displayed promise in disrupting formed aggregates of the peptide. These findings represent an exciting new avenue for therapeutic development in AD, where both sides of the aggregation equilibrium are affected.

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 β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 µM, 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 β-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 µM, and low or intermediate impairment of HFF viability at 2.5 µM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity.