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Design, synthesis, anti-acetylcholinesterase evaluation and molecular modelling studies of novel coumarin-chalcone hybrids.

  • Hasan, Aso Hameed1, 2
  • Shakya, Sonam3
  • Hussain, Faiq H S4
  • Murugesan, Sankaranarayanan5
  • Chander, Subhash6
  • Pratama, Mohammad Rizki Fadhil7, 8
  • Jamil, Shajarahtunnur1
  • Das, Basundhara9
  • Biswas, Subhrajit9
  • Jamalis, Joazaizulfazli1
  • 1 Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, Johor Bahru, Johor, Malaysia. , (Malaysia)
  • 2 Department of Chemistry, College of Science, University of Garmian, Kalar, Kurdistan Region-Iraq, Iraq. , (Iraq)
  • 3 Department of Chemistry, Faculty of Science, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. , (India)
  • 4 Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Kurdistan Region-Iraq, Iraq. , (Iraq)
  • 5 Medicinal Chemistry Research Laboratory, Birla Institute of Technology & Science Pilani (BITS Pilani), Pilani, Rajasthan, India. , (India)
  • 6 Amity Institute of Phytochemistry and Phytomedicine, Amity University Uttar Pradesh, Noida, Uttar Pradesh, India. , (India)
  • 7 Doctoral Program of Pharmaceutical Sciences, Universitas Airlangga, Surabaya, East Java, Indonesia. , (Indonesia)
  • 8 Department of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia. , (Indonesia)
  • 9 Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Translational Cancer & Stem Cell Research Laboratory, Noida, Uttar Pradesh, India. , (India)
Published Article
Journal of biomolecular structure & dynamics
Publication Date
Jan 01, 2023
DOI: 10.1080/07391102.2022.2162583
PMID: 36591704


The major enzyme responsible for the hydrolytic breakdown of the neurotransmitter acetylcholine (ACh) is acetylcholinesterase (AChE). Acetylcholinesterase inhibitors (AChEIs) are the most prescribed class of medications for the treatment of Alzheimer's disease (AD) and dementia. The limitations of available therapy, like side effects, drug tolerance, and inefficacy in halting disease progression, drive the need for better, more efficacious, and safer drugs. In this study, a series of fourteen novel chalcone-coumarin derivatives (8a-n) were designed, synthesized and characterized by spectral techniques like FT-IR, NMR, and HR-MS. Subsequently, the synthesized compounds were tested for their ability to inhibit acetylcholinesterase (AChE) activity by Ellman's method. All tested compounds showed AChE inhibition with IC50 value ranging from 0.201 ± 0.008 to 1.047 ± 0.043 μM. Hybrid 8d having chloro substitution on ring-B of the chalcone scaffold showed relatively better potency, with IC50 value of 0.201 ± 0.008 μM compared to other members of the series. The reference drug, galantamine, exhibited an IC50 at 1.142 ± 0.027 μM. Computational studies revealed that designed compounds bind to the peripheral anionic site (PAS), the catalytic active site (CAS), and the mid-gorge site of AChE. Putative binding modes, ligand-enzyme interactions, and stability of the best active compound are studied using molecular docking, followed by molecular dynamics (MD) simulations. The cytotoxicity of the synthesised derivatives was determined using the MTT test at three concentrations (100 g/mL, 500 g/mL, and 1 mg/mL). None of the chemicals had a significant effect on the body at the highest dose of 1 mg/mL.Communicated by Ramaswamy H. Sarma.

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