Isoindolone derivatives as novel potential anti-Alzheimer’s candidates: synthesis, in silico, and AChE inhibitory activity evaluation

Alzheimer’s disease (AD) is a neurodegenerative condition that affects elderly persons around the world, impairing cognitive function, due to a decrease in cholinergic transmission. Thus, developing drugs with better acetylcholinesterase (AChE) inhibitory characteristics will improve cholinergic transmission. This work aimed to synthesize isoindolone derivatives and test their AChE inhibitory activity both in silico and in vitro, and to compare them with their precursors. Seven racemic mixtures (isoindolones) and four precursors were synthesized in good yields. Their interaction with AChE is mainly mediated by the aromatic ring and the ester group, according to molecular docking. The in vitro experiments revealed competitive inhibition for all tested molecules. The structural analysis showed better Ki values for structures with an extra double bond, and the two ester groups. Racemic mixture rac-6 showed the lowest Ki (55.4 µM) of all compounds. Both aromatic ring moieties and two ester groups in the isoindolone derivatives play an important role in recognition with AChE. [Figure not available: see fulltext.]