Solid supported synthesis of pyrazinyl and oxindolyl tethered ferrocenyl conjugates with unusual rotational flexibility as promising inhibitors of HEWL amyloid fibrillation and cytotoxicity

Abstract

Aggregation of protein and formation of amyloid fibrils are not only associated with numerous neurodegenerative diseases, but also lead to non-neuropathic amyloidogenic diseases and systemic amyloidosis. Inhibition of fibrillar aggregates using flexible and functional molecules can present a promising strategy for restraining or preventing amyloid related diseases. In this study, a series of heterocyclic bi-functionalized ferrocenyl conjugates with rotational flexibility have been synthesized via solvent free reaction involving wastes, redmud and rice husk ash, as a solid support. These strategic associations of the heterocyclic framework with the rotationally flexible, electroactive ferrocenyl moiety led to a biocompatible molecular system with a significant role in protein interactions in the amyloid prone region. Therefore, the inhibitory potential of two such functional molecular systems, dipyrazinyl ferrocenyl dienone (3) and oxindolyl ferrocenyl chalcone (5), has been explored against hen egg white lysozyme (HEWL) amyloid fibrillation along with their disruptive effects on mature fibrils. Distinct inhibitory potency has been observed displaying strong interactions with protein residues in the amyloid prone region, possibly due to the unusual rotational flexibility feature of the molecules. In addition, the inhibitors showed significant protective effects against the cytotoxicity induced by aggregated amyloid fibrils in human leukemia monocytic cell lines (THP-1). The bi-functionalized redox-active inhibitor molecule (5) has also been explored as an electrochemical probe to monitor the stages of amyloid inhibition during the fibrillation process.