Novel 2-Amino-pyrano[3,2-c]quinoline-3-carbonitrile Derivatives Bearing Benzyloxy Phenyl Moiety as Butyrylcholinesterase Inhibitors: Design, Synthesis, In Vitro Evaluation, and Molecular Docking Studies

Alzheimer’s disease (AD), the main form of dementia, is a multifactorial neurodegenerative disease, and several hypotheses have been proposed for its pathogenesis. Among them, cholinergic hypofunction is the main reason and plays a significant role in cognitive impairment. According to this theory, ChE inhibitors improve the performance of the cholinergic system and increase memory function. Thus, this study investigated a novel series of 2-amino-pyrano[3,2-c]quinoline-3-carbonitrile derivatives bearing benzyloxy phenyl moiety as ChE enzyme inhibitors.

The synthesized compounds 6a-o are divided into three series based on benzyloxy phenyl moiety. The structure of all compounds was identified by the NMR (1H and 13C) and IR spectra. Then, their inhibitory activities against ChE enzymes were evaluated by Ellman’s spectrophotometrical method. The kinetic and molecular docking studies were performed for compound 6l as the most potent butyrylcholinesterase (BChE) inhibitor.

The 2-amino-4-(4-((4-fluorobenzyl)oxy)-3-methoxyphenyl)-5-oxo-5,6-dihydro-4H-pyrano[3,2-c] quinoline-3-carbonitrile (6l) demonstrated the best anti-BChE activity with a half maximal inhibitory concentration value of 1.00 ± 0.07. The kinetic and molecular docking studies confirmed that 6l is a mixed inhibitor and binds to both the anionic catalytic site and peripheral anionic site (PAS) of BChE. In silico study approved that the methoxy group on the middle phenyl ring has a significant role in interacting with the PAS of the enzyme.

These findings indicated that 2-amino-pyrano[3,2-c]quinoline-3-carbonitrile derivatives bearing benzyloxy phenyl moiety have therapeutic potential as BChE inhibitors in the last stages of AD.