Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors
A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory act...
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MDPI AG
2018-08-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/16/9/293 |
| _version_ | 1811191585707130880 |
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| author | Zhi-Qiang Cheng Jia-Li Song Kongkai Zhu Juan Zhang Cheng-Shi Jiang Hua Zhang |
| author_facet | Zhi-Qiang Cheng Jia-Li Song Kongkai Zhu Juan Zhang Cheng-Shi Jiang Hua Zhang |
| author_sort | Zhi-Qiang Cheng |
| collection | DOAJ |
| description | A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer’s disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development. |
| first_indexed | 2024-04-11T22:03:57Z |
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| id | doaj.art-37a9bb3a17294e2ca245df00fbdef97f |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T22:03:57Z |
| publishDate | 2018-08-01 |
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| series | Marine Drugs |
| spelling | doaj.art-37a9bb3a17294e2ca245df00fbdef97f2022-12-22T04:00:46ZengMDPI AGMarine Drugs1660-33972018-08-0116929310.3390/md16090293md16090293Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation InhibitorsZhi-Qiang Cheng0Jia-Li Song1Kongkai Zhu2Juan Zhang3Cheng-Shi Jiang4Hua Zhang5School of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Sciences, University of Brasília, Brasília 72220-275, BrazilSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaSchool of Biological Science and Technology, University of Jinan, Jinan 250022, ChinaA marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aβ aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer’s disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.http://www.mdpi.com/1660-3397/16/9/293pulmonarin Bbrominated-phenylacetic acid/tacrine hybridsacetylcholinesterasebutylcholinesteraseanti-amyloid aggregationAlzheimer’s disease |
| spellingShingle | Zhi-Qiang Cheng Jia-Li Song Kongkai Zhu Juan Zhang Cheng-Shi Jiang Hua Zhang Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors Marine Drugs pulmonarin B brominated-phenylacetic acid/tacrine hybrids acetylcholinesterase butylcholinesterase anti-amyloid aggregation Alzheimer’s disease |
| title | Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors |
| title_full | Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors |
| title_fullStr | Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors |
| title_full_unstemmed | Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors |
| title_short | Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aβ Aggregation Inhibitors |
| title_sort | total synthesis of pulmonarin b and design of brominated phenylacetic acid tacrine hybrids marine pharmacophore inspired discovery of new che and aβ aggregation inhibitors |
| topic | pulmonarin B brominated-phenylacetic acid/tacrine hybrids acetylcholinesterase butylcholinesterase anti-amyloid aggregation Alzheimer’s disease |
| url | http://www.mdpi.com/1660-3397/16/9/293 |
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