Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents
Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s c...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2021.1913137 |
| _version_ | 1829463861770584064 |
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| author | Sheunopa C. Mzezewa Sylvester I. Omoruyi Luke S. Zondagh Sarel F. Malan Okobi E. Ekpo Jacques Joubert |
| author_facet | Sheunopa C. Mzezewa Sylvester I. Omoruyi Luke S. Zondagh Sarel F. Malan Okobi E. Ekpo Jacques Joubert |
| author_sort | Sheunopa C. Mzezewa |
| collection | DOAJ |
| description | Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP+-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection. |
| first_indexed | 2024-12-13T13:38:06Z |
| format | Article |
| id | doaj.art-d4af1050d3ea43109b836387a213883e |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-13T13:38:06Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-d4af1050d3ea43109b836387a213883e2022-12-21T23:43:41ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-013611606162010.1080/14756366.2021.19131371913137Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agentsSheunopa C. Mzezewa0Sylvester I. Omoruyi1Luke S. Zondagh2Sarel F. Malan3Okobi E. Ekpo4Jacques Joubert5Department of Pharmaceutical Chemistry, School of Pharmacy, University of the Western CapeDepartment of Medical Biosciences, University of the Western CapeDepartment of Pharmaceutical Chemistry, School of Pharmacy, University of the Western CapeDepartment of Pharmaceutical Chemistry, School of Pharmacy, University of the Western CapeDepartment of Medical Biosciences, University of the Western CapeDepartment of Pharmaceutical Chemistry, School of Pharmacy, University of the Western CapeMultitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;µM. Significant neuroprotective effects towards MPP+-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection.http://dx.doi.org/10.1080/14756366.2021.1913137alzheimer’s diseasecoumarincholinesterasemonoamine oxidaseneuroprotection |
| spellingShingle | Sheunopa C. Mzezewa Sylvester I. Omoruyi Luke S. Zondagh Sarel F. Malan Okobi E. Ekpo Jacques Joubert Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents Journal of Enzyme Inhibition and Medicinal Chemistry alzheimer’s disease coumarin cholinesterase monoamine oxidase neuroprotection |
| title | Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents |
| title_full | Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents |
| title_fullStr | Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents |
| title_full_unstemmed | Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents |
| title_short | Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents |
| title_sort | design synthesis and evaluation of 3 7 substituted coumarin derivatives as multifunctional alzheimer s disease agents |
| topic | alzheimer’s disease coumarin cholinesterase monoamine oxidase neuroprotection |
| url | http://dx.doi.org/10.1080/14756366.2021.1913137 |
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