Promising Flavonoid-Fused Aminoquinolines as Synthetic Alzheimer's Disease Models: Design, Synthesis, Anticholinesterase Activity, ADMET and Molecular Docking.

An efficient one-pot, two-step [4 + 2] cyclocondensation reaction of (±)-2-phenylchroman-4-ones (1) with various scaffolds of 2-aminobenzonitriles (2) was employed using AlCl3 as the catalyst in the presence of toluene as a solvent under conventional thermal heating. This method was used to synthesize a series of six novel examples of (±)-7-amino-6-aryl-6H-chromeno[4,3-b]quinolines (3), which were designed as potential cholinesterase inhibitors. Subsequently, the new chromeno[4,3-b]quinolines were evaluated for their AChE and BChE inhibitory activity and subjected to molecular docking studies. In vitro cholinesterase assays and in silico docking demonstrated that all newly modified tacrine analogs 3 exhibited higher HsBChE inhibitory activity compared to HsAChE. Specifically, the most effective human cholinesterase inhibitor was the compound (±)-7-amino-6-phenyl-6H-chromeno[4,3-b]quinoline (3aa), with an IC50 of 2.73 μM for HsAChE and 0.096 μM for HsBChE. These findings suggest that compound 3aa is a promising candidate for further assessment in synthetic Alzheimer's disease models.