Molecular hybridization based design and synthesis of new benzo[5,6]chromeno[2,3-b]-quinolin-13(14H)-one analogs as cholinesterase inhibitors

Abstract

A Series of new tacrine analogs were designed, synthesized, characterized by respective spectral data and evaluated for cholinesterase inhibitory activity to be useful in Alzheimer’s disease. Most of the synthesized compounds showed good in vitro inhibitory activities toward acetyl cholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Among the compounds, 6i, 6o and 6r with increased saturated carboxylic ring size attached to the pyridine moiety and having 3,4-dihydroxy, 3,4,5-trimethoxy substituents on the aromatic ring attached at the stereogenic center have shown equal potency to that of tacrine with IC50values 0.65 ± 0.06, 1.32 ± 0.02 and 0.85 ± 0.05, 1.65 ± 0.12 and 0.92 ± 0.03, 1.91 ± 0.12 μM against AChE and BuChE, respectively. Standard drug tacrine exhibited IC50 values of 0.47 ± 0.02 and 0.65 ± 0.08, while Donepezil showed IC50 0.71 ± 0.06 and 0.31 ± 0.04 μM against AChE and BuChE, respectively. Docking studies of all the molecules disclosed close hydrogen bond interactions with the binding site.