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.

Automated summary

In this study, we synthesized seven new compounds and discovered that one of them exhibited significant acetylcholinesterase inhibitory activity and improved cognitive function in animal experiments. These results contribute to the design of new drugs for treating cognitive disorders.