Development of multifunctional heterocyclic Schiff base as a potential metal chelator: a comprehensive spectroscopic approach towards drug discovery.
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.
Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440010, Maharashtra, India.
Manojkumar
M
Jadhao
Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440010, Maharashtra, India.
Chayan
C
Das
Tata Institute of Fundamental Research (TIFR), 1-Homi Bhabha Road, Colaba, 400005, Mumbai, India.
Anoop
A
Rawat
Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440010, Maharashtra, India.
Himank
H
Kumar
Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440010, Maharashtra, India.
Ritika
R
Joshi
Tata Institute of Fundamental Research (TIFR), 1-Homi Bhabha Road, Colaba, 400005, Mumbai, India.
Sudipta
S
Maiti
Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, 440010, Maharashtra, India. sujitju@yahoo.co.in.
Sujit Kumar
SK
Ghosh
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017382:Reactive Oxygen Species / Q000378:metabolism; D012545:Schiff Bases / Q000737:chemistry; D013057:Spectrum Analysis
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D012545:Schiff Bases; C078592:amyloid beta-protein (1-40)
Amyloid beta; Electronic absorption; Schiff base; Single molecule fluorescence correlation spectroscopy; Steady-state fluorescence