Abstract
A novel scaffold of N-substituted (3-(1-aminoethylidene)-2-oxochroman-4-yl)phosphonic acid diethyl ester derivatives was designed, synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors against Alzheimer’s disease. Compounds 2a, 2b, 2d and 2q proved to be more potent than the standard drug galantamine and rivastigmine for AChE inhibitory activity with IC50 value between 0.50 and 3.94 µM. All the synthesized compounds proved to be only weak BuChE inhibitors. The compounds showed cytotoxicity in the same range as that of standard drugs against HEK-293 cells. Molecular docking studies suggested that compound 2q is acting as a dual binding site inhibitor by occupying the enzymatic catalytic active site, mid-gorge and peripheral anionic site. The coumarin moiety showed a π–π stacking interaction with Trp84 and hydrogen bonds with the P=O and C=O was found with Ser122 and Tyr121 at the catalytic active site. At the peripheral anionic site, the phenyl ring and quinoline ring were stacked against the Tyr 334 and Trp279 through π–π stacking interaction, respectively. The predicted ADME showed a good pharmacokinetic profile. DNA cleavage studies suggested that compounds 2a, 2b, 2d and 2q can be considered as non-toxic. Thus, compound 2q could be a promising lead structure for further development as anti-Alzheimer agents.
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Acknowledgements
One of the authors (Sarfaraz Shaikh) is thankful to DST-PURSE, New Delhi, for award of research fellowship. We are also thankful to Microanalytical Laboratory, Department of Chemistry and University of Mumbai, for providing characterization facilities. We are also thankful to Mr Pratik Dhavan (Department of Life sciences, University of Mumbai) for performing biological activities. The authors also thank Dr. Urmila J. Joshi and Miss Heena Bhojwani (Department of Pharmaceutical Chemistry, K. M. Kundnani College of Pharmacy, Cuffe Parade, Colaba, Mumbai, Maharashtra 400 005, India) for computer-aided drug design.
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Supplementary material 1 (DOCX 2285 kb) The NMR and MS spectra of compounds 2(a-q) are given in the Supporting Information
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Shaikh, S., Pavale, G. & Ramana, M.M.V. Synthesis and biological evaluation of novel N-substituted (3-(1-aminoethylidene)-2-oxochroman-4-yl)phosphonic acid diethyl ester derivatives as anti-Alzheimer agent. Chem. Pap. 74, 2555–2571 (2020). https://doi.org/10.1007/s11696-020-01099-0
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DOI: https://doi.org/10.1007/s11696-020-01099-0