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

Hasan, Aso Hameed and Shakya, Sonam and Hussain, Faiq H.S. and Murugesan, Sankaranarayanan and Chander, Subhash and Pratama, Mohammad Rizki Fadhil and Jamil, Shajarahtunnur and Das, Basundhara and Biswas, Subhrajit and Jamalis, Joazaizulfazli (2022) Design, synthesis, anti-acetylcholinesterase evaluation and molecular modelling studies of novel coumarin-chalcone hybrids. Journal of Biomolecular Structure and Dynamics. pp. 1-13.

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Official URL: https://www.tandfonline.com/doi/full/10.1080/07391...

Abstract

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.

Item Type: Article
Uncontrolled Keywords: Acetylcholinesterase; coumarin; chalcone; cytotoxicity; molecular modelling
Subjects: 600 Technology and Applied Sciences > 610 - 619 Medical and Medicine Science > 610 Medicine and Health
600 Technology and Applied Sciences > 610 - 619 Medical and Medicine Science > 610 Medicine and Health > 610.7 Research and Statistical Methods of Medical Science
Divisions: Perpustakaan > Journals
Depositing User: Publikasi Library UMPR
Date Deposited: 03 Apr 2023 12:49
Last Modified: 03 Apr 2023 12:49
URI: http://repository.umpr.ac.id/id/eprint/341

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