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

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 21; p. 7392
• Main Authors: Ramírez-Ruiz, Alma Marisol, Ávila-Cossío, Martha Elena, Estolano-Cobián, Arturo, Cornejo-Bravo, José Manuel, Martinez, Ana Laura, Córdova-Guerrero, Iván, Cota-Ramírez, Bibiana Roselly, Carranza-Ambriz, Krysta Paola, Rivero, Ignacio A., Serrano-Medina, Aracely
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.11.2023
• Subjects: Alzheimer's disease; Amino acids; Analysis; cinnamic acid; Drugs; Enzyme kinetics; human acetylcholinesterase; inhibitory activity; oxazolones; Mexico
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28217392

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 μM, showed an affinity (Ki) from 2 to 198 μM, and an IC50 from 9 to 246 μM. 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 μmol/kg) and an Object Recognition Test (10 μmol/kg). Our results can help the rational design of hAChE inhibitors to work as potential candidates for treating cognitive disorders.