Synthesis, biological evaluation and molecular modeling studies of modulated benzyloxychalcones as potential acetylcholinesterase inhibitors

Abstract

Acetylcholinesterase inhibitors (AChEIs) have become a significant target in the search for an efficient treatment of Alzheimer’s disease. Chalcone-based compounds display a strong potency to hinder AChE. So, this study focused on the synthesis of a series of new chalcone derivatives with anti-cholinesterase potential and their structures were characterized based on spectroscopic methods including IR, ¹H NMR, ¹³C NMR and HRMS. Chalcone derivatives were screened against AChE. Most of them exhibited potent inhibitory activity against AChE. Compound 11i showed the most potent activity toward acetylcholinesterase compared to the positive compound, Galantamine. Docking studies into the active site of the acetylcholinesterase enzyme ravealed the significant docking score of the synthesized compounds with docking score of −7.959 to −9.277 kcal/mol when compared to the co-crystallized ligand, Donepezil (−10.567 kcal/mol). The interaction’s stability was further assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 11i in the cavity of the acetylcholinesterase enzyme.

Communicated by Ramaswamy H. Sarma

Keywords:

• Acetylcholinesterase inhibitors
• chalcone
• molecular docking
• dynamics simulation

Authors’ contributions

The study in this manuscript was collaboratively executed by all aforementioned authors. Arman AbdallaAli: Wrote the manuscripts. Shakhawan Ahmad Mhamad: Wrote the manuscripts. Aso Hameed Hasan: Involve in molecular docking and reviewed the manuscript. Iqrar Ahmad: Involve in molecular dynamic (MD) simulation. Siti Awanis Abdullah: Involve in acetylcholinesterase inhibitory evaluation. Shajarahtunnur Jamil: Involve in acetylcholinesterase inhibitory evaluation. Harun Patel: Involve in molecular dynamic (MD) simulation. Sankaranarayanan Murugesan: Involve in molecular docking and reviewed the manuscript. Joazaizulfazli Jamalis: Involve in synthesis work, main supervisor of this project and reviewed the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors wish to thank the Ministry of Higher Education (MOHE) Malaysia for funding this research under the Fundamental Research Grant Scheme (FRGS/1/2022/STG04/UTM/02/4).