Novel Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer’s disease

17 March 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Neurodegenerative diseases such as Alzheimer’s diseases (AD) are associated with progressive neuronal cell death and a common correlation is aberrant protein misfolding and aggregation of the Aβ peptide. Transition metal ions (Cu, Fe and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two novel compounds (HL1 and HL2), the rationale behind the design, their synthesis, characterization and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aβ interacting moiety; whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Further, we went on exploring their multifunctionality w.r.t. to (i) their metal chelating capacities (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) scavenge free radicals, (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aβ-Cu complex and thus disrupt the redox cycle. Molecular docking studies were also performed with Aβ and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising anti-Alzheimer’s candidates.


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