Benzyloxychalcone Hybrids as Prospective Acetylcholinesterase Inhibitors against Alzheimer’s Disease: Rational Design, Synthesis, In Silico ADMET Prediction, QSAR, Molecular Docking, DFT, and Molecular Dynamic Simulation Studies
Al-Maqtari H.M. Hasan A.H. Suleiman M. Ahmad Zahidi M.A. Noamaan M.A. Alexyuk P. Alexyuk M. Bogoyavlenskiy A. Jamalis J.
2024American Chemical Society
ACS Omega
2024
Acetylcholinesterase inhibitors (AChEIs) are crucial therapeutic targets for both the early and severe stages of Alzheimer’s disease (AD). Chalcones and their chromone-based derivatives are well-known building blocks with anti-Alzheimer properties. This study synthesized 4-benzyloxychalcone derivatives and characterized their structures using IR, 1H NMR, 13C NMR, and HRMS. Additionally, the synthesized 4-benzyloxychalcone derivatives were tested for anti-acetylcholinesterase (AChE) activity. The synthesized compounds outperformed galantamine, which is used as a positive control against acetylcholinesterase. Utilizing an acetylcholinesterase (AChE) receptor (PDB ID: 4EY7)-chalcone derivative (12a-c), a molecular docking investigation was performed on the synthesized compounds. The goal was to predict the binding sites and energies of the derivatives with respect to the receptor amino acids. The dynamic behavior of the ligand-receptor complex resulting from the interaction of the best docking compounds 12a and 12c with the acetylcholinesterase receptor was used to analyze the stability via MD simulation. MM/GBSA and MM/PBSA were used to calculate free binding energies using snapshots from system trajectories. Advanced computational approaches incorporating long-range corrections were utilized to calculate the molecular characteristics of chalcone derivatives 12a-c at the DFT/wB97XD/6-311++G(d,p) level. We used the molecular electrostatic surface potential (MESP) with high-quality data and visualization to find the most active site in these molecules. Reactivity descriptors, including the condensed Fukui function, chemical hardness (η), dual descriptors, chemical potential (μ), and electrophilicity (ω), were calculated for the chalcone derivatives.
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Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, Johor, Johor Bahru, 81310, Malaysia
Department of Chemistry, College of Education, Hodeidah University, University, Hodeidah, Yemen
Department of Chemistry, College of Science, University of Garmian, Kurdistan Region, Kalar, 46021, Iraq
Department of Chemistry, Sokoto state university, Birnin Kebbi road, Sokoto, Sokoto, 852101, Nigeria
Mathematics Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
Research and Production Center for Microbiology and Virology, Almaty, 050010, Kazakhstan
Department of Chemistry
Department of Chemistry
Department of Chemistry
Department of Chemistry
Mathematics Department
Research and Production Center for Microbiology and Virology
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