Staff View: Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies

Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies

To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and...

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Main Authors:	Hasan, Aso Hameed, Abdulrahman, Faruq Azeez, Obaidullah, Ahmad J., Alotaibi, Hadil Faris, Alanazi, Mohammed M., Noamaan, Mahmoud A., Murugesan, Sankaranarayanan, Amran, Syazwani Itri, Bhat, Ajmal R., Jamalis, Joazaizulfazli
Format:	Article
Language:	English
Published:	MDPI 2023
Subjects:	Q Science (General)
Online Access:	http://eprints.utm.my/106207/1/SyazwaniItriAmran2023_DiscoveryofNovelCoumarinSchiffBase.pdf http://eprints.utm.my/106207/ http://dx.doi.org/10.3390/ph16070971
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spelling	my.utm.1062072024-06-20T02:06:49Z http://eprints.utm.my/106207/ Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies Hasan, Aso Hameed Abdulrahman, Faruq Azeez Obaidullah, Ahmad J. Alotaibi, Hadil Faris Alanazi, Mohammed M. Noamaan, Mahmoud A. Murugesan, Sankaranarayanan Amran, Syazwani Itri Bhat, Ajmal R. Jamalis, Joazaizulfazli Q Science (General) To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC50 values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC50 values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC50 of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems’ trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes. MDPI 2023-07 Article PeerReviewed application/pdf en http://eprints.utm.my/106207/1/SyazwaniItriAmran2023_DiscoveryofNovelCoumarinSchiffBase.pdf Hasan, Aso Hameed and Abdulrahman, Faruq Azeez and Obaidullah, Ahmad J. and Alotaibi, Hadil Faris and Alanazi, Mohammed M. and Noamaan, Mahmoud A. and Murugesan, Sankaranarayanan and Amran, Syazwani Itri and Bhat, Ajmal R. and Jamalis, Joazaizulfazli (2023) Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies. Pharmaceuticals, 16 (7). pp. 1-33. ISSN 1424-8247 http://dx.doi.org/10.3390/ph16070971 DOI:10.3390/ph16070971
institution	Universiti Teknologi Malaysia
building	UTM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Teknologi Malaysia
content_source	UTM Institutional Repository
url_provider	http://eprints.utm.my/
language	English
topic	Q Science (General)
spellingShingle	Q Science (General) Hasan, Aso Hameed Abdulrahman, Faruq Azeez Obaidullah, Ahmad J. Alotaibi, Hadil Faris Alanazi, Mohammed M. Noamaan, Mahmoud A. Murugesan, Sankaranarayanan Amran, Syazwani Itri Bhat, Ajmal R. Jamalis, Joazaizulfazli Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
description	To discover anti-acetylcholinesterase agents for the treatment of Alzheimer’s disease (AD), a series of novel Schiff base-coumarin hybrids was rationally designed, synthesized successfully, and structurally characterized using Fourier transform infrared (FTIR), Nuclear magnetic resonance (NMR), and High-Resolution Mass Spectrometry (HRMS) analyses. These hybrids were evaluated for their potential inhibitory effect on acetylcholinesterase (AChE). All of them exhibited excellent inhibitory activity against AChE. The IC50 values ranged from 87.84 to 515.59 μg/mL; hybrids 13c and 13d with IC50 values of 0.232 ± 0.011 and 0.190 ± 0.004 µM, respectively, showed the most potent activity as acetylcholinesterase inhibitors (AChEIs). The reference drug, Galantamine, yielded an IC50 of 1.142 ± 0.027 µM. Reactivity descriptors, including chemical potential (μ), chemical hardness (η), electrophilicity (ω), condensed Fukui function, and dual descriptors are calculated at wB97XD/6-311++ G (d,p) to identify reactivity changes of the designed compounds. An in-depth investigation of the natural charge pattern of the studied compounds led to a deep understanding of the important interaction centers between these compounds and the biological receptors of AChE. The molecular electrostatic surface potential (MESP) of the most active site in these derivatives was determined using high-quality information and visualization. Molecular docking analysis was performed to predict binding sites and binding energies. The structure-activity-property relationship studies indicated that the proposed compounds exhibit good oral bioavailability properties. To explore the stability and dynamic behavior of the ligand-receptor complexes, molecular dynamics simulations (MDS) were performed for 100 ns on the two best docked derivatives, 13c and 13d, with the AChE (4EY7) receptor. A popular method for determining the free binding energies (MM/GBSA) is performed using snapshots taken from the systems’ trajectories at 100 ns. These results revealed that the complex system of compound 13d acquired a relatively more stable conformation and exhibited better descriptors than the complex system of compound 13c and the Galantamine drug, suggesting its potential as an effective inhibiting drug. The binding free energy analysis revealed that the 13d-4EY7 complex exhibited greater stability with AChE receptors compared to other complexes.
format	Article
author	Hasan, Aso Hameed Abdulrahman, Faruq Azeez Obaidullah, Ahmad J. Alotaibi, Hadil Faris Alanazi, Mohammed M. Noamaan, Mahmoud A. Murugesan, Sankaranarayanan Amran, Syazwani Itri Bhat, Ajmal R. Jamalis, Joazaizulfazli
author_facet	Hasan, Aso Hameed Abdulrahman, Faruq Azeez Obaidullah, Ahmad J. Alotaibi, Hadil Faris Alanazi, Mohammed M. Noamaan, Mahmoud A. Murugesan, Sankaranarayanan Amran, Syazwani Itri Bhat, Ajmal R. Jamalis, Joazaizulfazli
author_sort	Hasan, Aso Hameed
title	Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
title_short	Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
title_full	Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
title_fullStr	Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
title_full_unstemmed	Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
title_sort	discovery of novel coumarin-schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies
publisher	MDPI
publishDate	2023
url	http://eprints.utm.my/106207/1/SyazwaniItriAmran2023_DiscoveryofNovelCoumarinSchiffBase.pdf http://eprints.utm.my/106207/ http://dx.doi.org/10.3390/ph16070971
_version_	1802977240362778624
score	13.211869

Discovery of novel Coumarin-Schiff base hybrids as potential acetylcholinesterase inhibitors: design, synthesis, enzyme inhibition, and computational studies

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