A Novel Donepezil–Caffeic Acid Hybrid: Synthesis, Biological Evaluation, and Molecular Docking Studies

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Derya Kılıçaslan^1,a*, Akif Hakan Kurt², Muhammet Köse³, Mustafa Çeşme³, Özge Güngör³, Cansu Kara Oztabag⁴, and Adem Doganer⁵

¹Afsin Vocational School, Department of Chemistry and Chemical Processing Technologies, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey

²Department of Pharmacology, Faculty of Medicine, Bolu Abant Izzet Baysal University, Bolu, Turkey

³Department of Chemistry, Faculty of Art and Sciences, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey

⁴Department of Interdisciplinary Neuroscience, Bolu Abant Izzet Baysal University, Institute of Health Sciences, Bolu, Turkey

⁵Department Biostatistics and Medical Informatics, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey

^* To whom correspondence should be addressed.

Received July 10, 2022; Revised December 30, 2022; Accepted January 4, 2023

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A novel donepezil–caffeic acid (DP-CA) hybrid molecule was designed, synthesis, and investigated by molecular modeling. Its biological activity and protective effect were investigated by the IR spectroscopy, ¹H and ¹³C NMR spectroscopy, and mass spectrometry. DP-CA was highly active against acetylcholine esterase and inhibited it at the micromolar concentrations. Fluorescence and UV-Vis spectroscopy studies showed strong binding of DP-CA to DNA. Moreover, DP-CA exhibited protective effects against H₂O₂-induced toxicity in U-118 MG glioblastoma cells. Finally, molecular docking showed a high affinity of DP-CA in all concentrations, and the active 4EY7 site exhibited essential residues with polar and apolar contacts. Taken together, these findings indicate that DP-CA could be a prospective multifunctional agent for the treatment of neurodegenerative diseases.

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KEY WORDS: donepezil, caffeic acid, hybrid molecule, acetylcholinesterase, molecular docking, protective effect

DOI: 10.1134/S0006297923010054

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