Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions
Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d, 5j, and 5 m showed a moderate ant...
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Wiley-VCH Verlag
2019
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| author | Kara, Jiraporn Suwanhom, Paptawan Wattanapiromsakul, Chatchai Nualnoi, Teerapat Puripattanavong, Jindaporn Khongkow, Pasarat Lee, Vannajan Sanghiran Gaurav, Anand Lomlim, Luelak |
| author_facet | Kara, Jiraporn Suwanhom, Paptawan Wattanapiromsakul, Chatchai Nualnoi, Teerapat Puripattanavong, Jindaporn Khongkow, Pasarat Lee, Vannajan Sanghiran Gaurav, Anand Lomlim, Luelak |
| author_sort | Kara, Jiraporn |
| collection | UM |
| description | Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329. The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2-oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents. © 2019 Deutsche Pharmazeutische Gesellschaft |
| first_indexed | 2024-03-06T06:02:03Z |
| format | Article |
| id | um.eprints-24187 |
| institution | Universiti Malaya |
| last_indexed | 2024-03-06T06:02:03Z |
| publishDate | 2019 |
| publisher | Wiley-VCH Verlag |
| record_format | dspace |
| spelling | um.eprints-241872020-04-09T05:40:41Z http://eprints.um.edu.my/24187/ Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions Kara, Jiraporn Suwanhom, Paptawan Wattanapiromsakul, Chatchai Nualnoi, Teerapat Puripattanavong, Jindaporn Khongkow, Pasarat Lee, Vannajan Sanghiran Gaurav, Anand Lomlim, Luelak Q Science (General) QD Chemistry Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329. The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2-oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents. © 2019 Deutsche Pharmazeutische Gesellschaft Wiley-VCH Verlag 2019 Article PeerReviewed Kara, Jiraporn and Suwanhom, Paptawan and Wattanapiromsakul, Chatchai and Nualnoi, Teerapat and Puripattanavong, Jindaporn and Khongkow, Pasarat and Lee, Vannajan Sanghiran and Gaurav, Anand and Lomlim, Luelak (2019) Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions. Archiv der Pharmazie / Chemistry in Life Sciences, 352 (7). p. 1800310. ISSN 0365-6233, DOI https://doi.org/10.1002/ardp.201800310 <https://doi.org/10.1002/ardp.201800310>. https://doi.org/10.1002/ardp.201800310 doi:10.1002/ardp.201800310 |
| spellingShingle | Q Science (General) QD Chemistry Kara, Jiraporn Suwanhom, Paptawan Wattanapiromsakul, Chatchai Nualnoi, Teerapat Puripattanavong, Jindaporn Khongkow, Pasarat Lee, Vannajan Sanghiran Gaurav, Anand Lomlim, Luelak Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| title | Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| title_full | Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| title_fullStr | Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| title_full_unstemmed | Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| title_short | Synthesis of 2‐(2‐oxo‐2 H ‐chromen‐4‐yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| title_sort | synthesis of 2 2 oxo 2 h chromen 4 yl acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions |
| topic | Q Science (General) QD Chemistry |
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