ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Synthesis and biological evaluation of novel N-substituted (3-(1-aminoethylidene)-2-oxochroman-4-yl)phosphonic acid diethyl ester derivatives as anti-Alzheimer agent

Sarfaraz Shaikh, Ganesh Pavale, and M. M. V. Ramana

Department of Chemistry, University of Mumbai, Mumbai, India

E-mail: mmvramana@yahoo.co.in

Received: 3 October 2019  Accepted: 10 February 2020

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.

Graphic Abstract:

Keywords: Acetylcholinesterase inhibitors; Cytotoxicity; Molecular docking; DNA cleavage

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01099-0

Chemical Papers 74 (8) 2555–2571 (2020)