Synthesis and Evaluation of chromen [4,3-b]chromenon Derivatives as AChE inhibitors

A series of chromene-fused coumarins namely 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-diones4a-o were synthesized using one-pot reaction of appropriate benzaldehyde, dimedone and 4-hydroxycoumarin, in the presence of nano-silica sulphuric acid under solvent-free condition in good yields. The in vitro anticholinesterase assay revealed that the 3-hydroxyphenyl analog 4e had the highest inhibitory activity against both AChE and BuChE, possessing IC50 values of 3.28 and 2.19 μM, respectively. The structure-activity relationships study demonstrated that the selectivity for AChE over BuChE could be modulated by introducing second hydroxy or methoxy substituent on the para-position of the 3-hydroxyphenyl pendent group. The docking study of compound 4e with AChE revealed that the coumarin nucleus of the molecule bounds with Trp279 via π-π stacking, and 3-hydroxy group forms hydrogen bond with Asn85.

کلیدواژه ها:

Alzheimer's disease ، Acetylcholinesterase ، Coumarin-fused derivatives ، One-pot synthesis ، Multicomponent reactions