Inhibitory Activity of 4-Benzylidene Oxazolones Derivatives of Cinnamic Acid on Human Acetylcholinesterase and Cognitive Improvements in a Mouse Model

We synthesized seven (Z)-benzylidene-2-(E)-styryloxazol-5(4H)-ones derivatives of cinnamic acid and evaluated the ability of these compounds to inhibit human acetylcholinesterase (hAChE). The most potent compound was evaluated for cognitive improvement in short-term memory. The seven compounds reversibly inhibited the hAChE between 51 and 75% at 300 mu M, showed an affinity (Ki) from 2 to 198 mu M, and an IC50 from 9 to 246 mu M. Molecular docking studies revealed that all binding moieties are involved in the non-covalent interactions with hAChE for all compounds. In addition, in silico pharmacokinetic analysis was carried out to predict the compounds' blood-brain barrier (BBB) permeability. The most potent inhibitor of hAChE significantly improved cognitive impairment in a modified Y-maze test (5 mu mol/kg) and an Object Recognition Test (10 mu mol/kg). Our results can help the rational design of hAChE inhibitors to work as potential candidates for treating cognitive disorders.