Ramirez-Ruiz_2023_Molecules_28_

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 microM, showed an affinity (K(i)) from 2 to 198 microM, and an IC(50) from 9 to 246 microM. 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 micromol/kg) and an Object Recognition Test (10 micromol/kg). Our results can help the rational design of hAChE inhibitors to work as potential candidates for treating cognitive disorders.