Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor
Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for Alzheimer's diseases, prompting immense research for novel and efficient small-molecule inhibitors. In this context, the present study describes the synthesis, characterization and evaluation of novel ether-lin...
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Elsevier
2025-12-01
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| Series: | European Journal of Medicinal Chemistry Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417425000457 |
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| author | Naseer Ahmad Dar Owais Hassan Wani Yuanyuan Wang Faez Iqbal Khan Bilal A. Ganie Syed Wajaht A. Shah Tanveer Ali Dar Tabasum Ismail |
| author_facet | Naseer Ahmad Dar Owais Hassan Wani Yuanyuan Wang Faez Iqbal Khan Bilal A. Ganie Syed Wajaht A. Shah Tanveer Ali Dar Tabasum Ismail |
| author_sort | Naseer Ahmad Dar |
| collection | DOAJ |
| description | Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for Alzheimer's diseases, prompting immense research for novel and efficient small-molecule inhibitors. In this context, the present study describes the synthesis, characterization and evaluation of novel ether-linked 3-acetyl triazole-substituted coumarin derivatives as potential AChE inhibitors. The synthetic route involved 3-acetyl-7-hydroxycoumarin preparation through the reaction of 2,4-dihydoxybenzaldehyde with ethyl acetoacetate. Following alkylation at hydroxyl group, the acetylated 7-hydroxycoumarin underwent 1,3-dipolar cycloaddition i.e., Huisgen cycloaddition with various aromatic azides under sharpless click chemistry conditions, leading to the formation of a library of 16 novel coumarin tethered 1,2,3-triazole derivatives. Following synthesis and characterization using 1H NMR, 13C NMR and IR spectroscopy, the AChE inhibitory potential of the coumarin derivatives was assessed, yielding IC50 value in the range of 2.18 μM–67.89 μM. Among them, compound 9 exhibited the most potent inhibition (IC50 = 2.18 μM), although lower than that of the standard inhibitor, eserine. Kinetic analysis indicated that compound 9 acted as a mixed-type inhibitor, with a Ki of 8.13 ± 0.18 μM. In silico simulation analysis elucidated the critical interactions between compound 9 and key AChE residues, including hydrogen bonding with Tyr121 and His444 and π-π stacking with Tyr334 and Trp283, supporting its strong binding affinity for the enzyme. Furthermore, the binding free energy calculations also confirmed the favourable thermodynamic interactions between the compound 9 and AChE. Collectively, the present findings highlight the therapeutic potential of compound 9 and establish this novel coumarin-triazole scaffold as a promising lead candidate for further optimization in development of AChE-targeted Alzheimer's therapeutics. |
| format | Article |
| id | doaj-art-8c4e3378a9ba4da2898bfeff9c2feba3 |
| institution | DOAJ |
| issn | 2772-4174 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj-art-8c4e3378a9ba4da2898bfeff9c2feba32025-08-20T03:14:36ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742025-12-011510028910.1016/j.ejmcr.2025.100289Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitorNaseer Ahmad Dar0Owais Hassan Wani1Yuanyuan Wang2Faez Iqbal Khan3Bilal A. Ganie4Syed Wajaht A. Shah5Tanveer Ali Dar6Tabasum Ismail7Department of Chemistry, University of Kashmir, Srinagar, 190006, Jammu and Kashmir, IndiaDepartment of Clinical Biochemistry, University of Kashmir, Srinagar, 190006, Jammu and Kashmir, IndiaDepartment of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, 111 Ren'ai Road, SIP, Suzhou, Jiangsu Province, 215123, PR ChinaDepartment of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, 111 Ren'ai Road, SIP, Suzhou, Jiangsu Province, 215123, PR ChinaSchool of Chemistry, University of Hyderabad, Hyderabad, 500046, IndiaDepartment of Chemistry, University of Kashmir, Srinagar, 190006, Jammu and Kashmir, IndiaDepartment of Clinical Biochemistry, University of Kashmir, Srinagar, 190006, Jammu and Kashmir, India; Corresponding author.Government Degree College, Pulwama, 192301, Jammu and Kashmir, India; Corresponding author.Acetylcholinesterase (AChE) inhibition remains an important therapeutic strategy for Alzheimer's diseases, prompting immense research for novel and efficient small-molecule inhibitors. In this context, the present study describes the synthesis, characterization and evaluation of novel ether-linked 3-acetyl triazole-substituted coumarin derivatives as potential AChE inhibitors. The synthetic route involved 3-acetyl-7-hydroxycoumarin preparation through the reaction of 2,4-dihydoxybenzaldehyde with ethyl acetoacetate. Following alkylation at hydroxyl group, the acetylated 7-hydroxycoumarin underwent 1,3-dipolar cycloaddition i.e., Huisgen cycloaddition with various aromatic azides under sharpless click chemistry conditions, leading to the formation of a library of 16 novel coumarin tethered 1,2,3-triazole derivatives. Following synthesis and characterization using 1H NMR, 13C NMR and IR spectroscopy, the AChE inhibitory potential of the coumarin derivatives was assessed, yielding IC50 value in the range of 2.18 μM–67.89 μM. Among them, compound 9 exhibited the most potent inhibition (IC50 = 2.18 μM), although lower than that of the standard inhibitor, eserine. Kinetic analysis indicated that compound 9 acted as a mixed-type inhibitor, with a Ki of 8.13 ± 0.18 μM. In silico simulation analysis elucidated the critical interactions between compound 9 and key AChE residues, including hydrogen bonding with Tyr121 and His444 and π-π stacking with Tyr334 and Trp283, supporting its strong binding affinity for the enzyme. Furthermore, the binding free energy calculations also confirmed the favourable thermodynamic interactions between the compound 9 and AChE. Collectively, the present findings highlight the therapeutic potential of compound 9 and establish this novel coumarin-triazole scaffold as a promising lead candidate for further optimization in development of AChE-targeted Alzheimer's therapeutics.http://www.sciencedirect.com/science/article/pii/S27724174250004573-Acetyl-7-hydroxy coumarinAlzheimer'sIn silico simulationLigand-enzyme complexEnzyme inhibition |
| spellingShingle | Naseer Ahmad Dar Owais Hassan Wani Yuanyuan Wang Faez Iqbal Khan Bilal A. Ganie Syed Wajaht A. Shah Tanveer Ali Dar Tabasum Ismail Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor European Journal of Medicinal Chemistry Reports 3-Acetyl-7-hydroxy coumarin Alzheimer's In silico simulation Ligand-enzyme complex Enzyme inhibition |
| title | Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor |
| title_full | Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor |
| title_fullStr | Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor |
| title_full_unstemmed | Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor |
| title_short | Novel triazole-based coumarin compounds as acetylcholinesterase inhibitors: Evidence and mechanism of 3-acetyl coumarin tethered (2-bromophenyl)-1,2,3 triazole as a potential mixed type inhibitor |
| title_sort | novel triazole based coumarin compounds as acetylcholinesterase inhibitors evidence and mechanism of 3 acetyl coumarin tethered 2 bromophenyl 1 2 3 triazole as a potential mixed type inhibitor |
| topic | 3-Acetyl-7-hydroxy coumarin Alzheimer's In silico simulation Ligand-enzyme complex Enzyme inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S2772417425000457 |
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