Conventional Organic Solvents And Ionic Liquid Mediated Synthesis Of New Azomethine Compounds As Potent Cholinesterase Inhibitors
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Date
2016-01
Authors
M. Abd Razik, Basma
Journal Title
Journal ISSN
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Publisher
Universiti Sains Malaysia
Abstract
Five new series of azomethine derivatives were synthesized by condensation of substituted benzaldehydes and amino derivatives in ethanol a conventional organic solvents and a green ionic solvent, 1-butyl-3-methylimidazolium bromide ([bmim]Br), respectively. The green ionic solvent [bmim]Br, due to its remarkable catalytic effect has several remarkable advantages over ethanol in terms of high product yields and short reaction time. Condensation reactions performed in an ionic solvent had resulted in a significant increase in product yields ranging from 18 to 29 % and 6-15 times decrease in reaction time as compared to similar reactions performed in ethanol. The azomethines were characterized using elemental analysis, FT-IR, 1-D and 2-D NMR spectroscopy as well as X-Ray crystallography. The synthesized compounds were also evaluated for their potency against Alzheimer’s disease using the Ellman’s colorimetric assay. In this assay, the cholinesterase inhibitory activities of the aforementioned compounds were screened in vitro against acetylcholinesterase (AChE) of electric eel and butyrylcholinesterase (BChE) extracted from equine serum, both of which play a major role in the manifestation and progression of Alzheimer’s disease. The results revealed that azomethine derivatives in series 9 displayed relatively better AChE inhibitory activities than those in series 3, 5, 7 and 11. This observation is presumably due to the presence of three aromatic cores in compounds series 9, which may facilitate the insertion and accommodation of these compounds in the AChE active site gorge. However, compounds of series 5 are also composed of three aromatic cores, but the presence of a carbonyl moiety in the structure of these molecules plausibly hinders their insertion and positioning in the active site gorge of the AChE enzyme. Besides, in term of AChE inhibition compounds 3g, 3j, 5j, 7f, 7g, 7j, 9f, 9h, and 11h showed high inhibitory activities which are comparable to the inhibitory activity of the standard drug, galanthamine. A similar observation was seen for compounds 3j, 5j, 7j, 9h and 11j in BChE inhibition. An in-silico molecular modeling analysis was also employed by using the crystal structure of Torpedo californica AChE (TcAChE) and human BChE (hBChE) to disclose the orientation and binding interaction mechanism of the active compounds inside the active site gorge of AChE and BChE receptors, respectively. Molecular dynamics (MD) simulation on silicon were used to obtain information in order to characterize the interactions between the active compounds and the related protein AChE and BChE, respectively. The stability of the ligand-protein complexes was evaluated based on their root mean square deviation (RMSD). In this study, the RMSD values of the active compounds, which complexed with AChE and BChE, respectively are less than those of the uncomplexed cholinesterase enzymes. This result indicates that the conformations of the ligand-protein complexes had achieved equilibrium and exhibit low fluctuation due to strongly tied up and binding with related proteins, thus leading to the inhibition of the cholinesterase enzymes. All these results are consistent with the observation in the biological assays.
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Keywords
Azomethines