Design and synthesis of piano-stool ruthenium(II) complexes and their studies on the inhibition of amyloid β (1–42) peptide aggregation.

Misfolding and protein aggregation have been linked to numerous human neurodegenerative disorders such as Alzheimer's, prion, and Parkinson's diseases. Ruthenium (Ru) complexes have received considerable attention in studying protein aggregation due to their interesting photophysical and photo properties. In this study, we have synthesized the novel Ru complexes ([ Ru(p-cymene)Cl(L-1)][PF 6 ](Ru-1), and [Ru(p-cymene)Cl(L-2)][PF 6 ](Ru-2)) and investigated their inhibitory activity against the bovine serum albumin (BSA) aggregation and the Aβ 1 – 42 peptides amyloid formation. Several spectroscopic methods were used to characterize these complexes, and the molecular structure of the complex was determined by X-ray crystallography. Amyloid aggregation and inhibition activities were examined using the Thioflavin-T (ThT) assay, and the secondary structures of the protein were analyzed by circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The cell viability assay was carried out on the neuroblastoma cell line, revealing that the complex Ru-2 showed better protective effects against A β 1 – 42 peptide toxicity on neuro-2a cells than the complex Ru-1. Molecular docking studies elucidate the binding sites and interactions between the Ru-complexes and Aβ 1 – 42 peptides. The experimental studies revealed that these complexes significantly inhibited the BSA aggregation and Aβ 1 – 42 amyloid fibril formation at 1:3 and 1:1 molar concentrations, respectively. Antioxidant assays demonstrated that these complexes act as antioxidants, protecting from amyloid-induced oxidative stress. Molecular docking studies with the monomeric A β 1 – 42 (PDB: 1IYT) show hydrophobic interaction, and both complexes bind preferably in the central region of the peptide and coordinate with two binding sites of the peptide. Hence, we suggest that the Ru-based complexes could be applied as a potential agent in metallopharmaceutical research against Alzheimer's disease. The piano-stool imine-based ruthenium (II) complexes applied for in vitro anti-Alzheimer's activity against the amyoid β peptides. Both the complexes significantly inhibited the aggregation and amyloid fibril formation by interacting with amyloid fibrils. They have also possess antioxidant properties which protect amyloid-induced oxidative stress and restricted fibril formation. [Display omitted] • Piano-stool ruthenium (II) complexes were designed and synthesized. • Molecular structure of the complex was determined by X-ray crystallography. • In vitro and in silico anti-Alzheimer's activities were performed. • Ruthenium complexes interact with amyloid peptides and inhibit the Aβ-aggregation. • Antioxidant properties of the complexes reduced the amyloid-induced oxidative stress. [ABSTRACT FROM AUTHOR]