In vitro studies of a series of synthetic compounds for their anti-acetylcholinesterase activities identified arylpyrano[2,3-f]coumarins as hit compounds

•A library of seventy-two synthetic compounds.•Evaluation for their inhibitory effects on acetylcholinesterase.•Pyranocoumarins showed the most potent inhibition.•Molecular docking revealed interesting interactions. Alzheimer's disease is one of the most widespread neurodegenerative diseases in the world. Until now, the drugs used to control this disease have been developed to target acetylcholinesterase (AChE). With the aim to identify new pharmacophores that can promisingly inhibit this enzyme, a library of 72 compounds belonging to chalcones, pyranochromenes, chromenes, pyranopyrazoles and dihydropyridines, was evaluated against AChE. Nineteen of these compounds are newly reported and among the tested compounds, seven, bearing a pyranochromene skeleton, showed inhibitory effects with IC50 values ranging from 9.01 to 32.39 µM. The most potent was identified as 8-amino-10-(4-bromophenyl)-5‑hydroxy-4-methyl-2-oxo-2,10-dihydropyrano[2,3-f]chromeno-9-carbonitrile. In silico studies using human recombinant acetylcholinesterase (PDB: 4EY7) showed important proximities between the NH2 group of this compound and E202 in AChE, between W86 and the OH-5 group, between W86 and the aromatic bicyclic system (π-π stacking, 4.2 Å), and between Y133 and both the OH-7 and the NH2 groups. These pyranochromenes emerged as a promising prototype for the development of new candidates against AChE. [Display omitted]