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Development of multifunctional heterocyclic Schiff base as a potential metal chelator: a comprehensive spectroscopic approach towards drug discovery

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Abstract

Amyloid-β peptides and their metal-associated aggregated states have been implicated in the pathogenesis of Alzheimer’s disease. The present paper epitomises the design and synthesis of a small, neutral, lipophilic benzothiazole Schiff base (E)-2-((6-chlorobenzo[d]thiazol-2-ylimino)methyl)-5-diethylamino)phenol (CBMDP), and explores its multifunctionalty as a potential metal chelator/fluorophore using UV–visible absorption, steady-state fluorescence, single molecule fluorescence correlation spectroscopic (FCS) techniques which is further corroborated by in silico studies. Some pharmaceutically relevant properties of the synthesized compound have also been calculated theoretically. Steady-state fluorescence and single molecule FCS reveal that the synthesized CBMDP not only recognizes oligomeric Aβ40, but could also be used as an amyloid-specific extrinsic fluorophore as it shows tremendous increase in its emission intensity in the presence of Aβ40. Molecular docking exercise and MD simulation reveal that CBMDP localizes itself in the crucial amyloidogenic and copper-binding region of Aβ40 and undergoes a strong binding interaction via H-bonding and π–π stacking. It stabilizes the solitary α-helical Aβ40 monomer by retaining the initial conformation of the Aβ central helix and mostly interacts with the hydrophilic N-terminus and the α-helical region spanning from Ala-2 to Val-24. CBMDP exhibits strong copper as well as zinc chelation ability and retards the rapid copper-induced aggregation of amyloid peptide. In addition, CBMDP shows radical scavenging activity which enriches its functionality. Overall, the consolidated in vitro and in silico results obtained for the synthesized molecule could provide a rational template for developing new multifunctional agents.

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Acknowledgements

SKG gratefully acknowledges the financial support from the Department of Science and Technology, India (Project no. SR/FT/LS/-172/2009) MJ thanks VNIT for his fellowship. The authors thank G. Krishnamoorthy, TIFR Mumbai, for providing steady-state fluorescence facility. The authors appreciate and thank the anonymous reviewers and the respected editor for their kind suggestions to improve the quality of the manuscript.

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Authors and Affiliations

  1. Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440010, Maharashtra, India

    Manojkumar Jadhao, Chayan Das, Himank Kumar, Ritika Joshi & Sujit Kumar Ghosh

  2. Tata Institute of Fundamental Research (TIFR), 1-Homi Bhabha Road, Colaba, 400005, Mumbai, India

    Anoop Rawat & Sudipta Maiti

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  1. Manojkumar Jadhao
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Jadhao, M., Das, C., Rawat, A. et al. Development of multifunctional heterocyclic Schiff base as a potential metal chelator: a comprehensive spectroscopic approach towards drug discovery. J Biol Inorg Chem 22, 47–59 (2017). https://doi.org/10.1007/s00775-016-1407-2

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