Abstract

Destabilization of protein's native conformation to intermediates rich in β-sheet structure may lead to amyloid fibrillation involving a complex process of aggregation that are primarily responsible for various neurodegenerative disorders. Design of flexible, functional molecules capable of disruption or inhibition of fibrillar aggregates at their initial stages can be an effective approach to restrict or prevent amyloid related diseases. In this perspective, strategic association of ferrocenyl based electro-active moiety with heterocyclic rings can generate flexible, biocompatible molecular system with significant role in protein interactions, electrochemical monitoring and improved biological activity. Therefore, synthesis of molecules containing multi-pyridine ring framework conjugated to a ferrocenyl scaffold have been explored using a unique solid state, redmud supported, solvent free reaction method which led to the formation of ferrocenyl bis-pyridylenone (2) and a rare class of ferrocene based 1,4-Michael addition compound (3). The 1,4-Michael addition attack at an olefinic carbon with bulkier, electron donating ferrocenyl substituent has been unprecedented. Inhibitory potential of di-functionalized ferrocenyl-bispyridylenone conjugate (2) against amyloid fibrillation and its ability to serve as electrochemical probe on the disaggregation process of BSA have been explored. The study revealed significant inhibition of amyloid fibrils during aggregation process and also showed disruption of pre-formed BSA fibrils. The redox active inhibitor molecule was also used as potential electrochemical probe to monitor the inhibition of the fibrillation process. Molecular dynamics simulation confirmed distinct hydrogen bond interactions between the inhibitor compound and the A chain of BSA and revealed enough conformational stability of the protein-inhibitor complex.

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