Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities
The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetyl...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/5/1303 |
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| author | Yingda Zang Ke Liu Weiping Wang Chuangjun Li Jie Ma Jingzhi Yang Xinyi Chen Xiaoliang Wang Dongming Zhang |
| author_facet | Yingda Zang Ke Liu Weiping Wang Chuangjun Li Jie Ma Jingzhi Yang Xinyi Chen Xiaoliang Wang Dongming Zhang |
| author_sort | Yingda Zang |
| collection | DOAJ |
| description | The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC<sub>50</sub>) 1.63–4.62 μM). Moreover, (<i>E</i>)-3-(8-(<i>tert</i>-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-<i>N</i>-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (<b>6bd</b>) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, <b>6bd</b> could cross the blood–brain barrier in vitro. More importantly, compared to edaravone, <b>6bd</b> had stronger free-radical scavenging activity. Molecular docking studies revealed that <b>6bd</b> could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate <b>6bd</b> as a leading structure worthy of further investigation. |
| first_indexed | 2024-03-09T06:11:32Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T06:11:32Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-5f409033732646dd880831ea6113ac9b2023-12-03T11:58:22ZengMDPI AGMolecules1420-30492021-02-01265130310.3390/molecules26051303Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective ActivitiesYingda Zang0Ke Liu1Weiping Wang2Chuangjun Li3Jie Ma4Jingzhi Yang5Xinyi Chen6Xiaoliang Wang7Dongming Zhang8State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaThe multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC<sub>50</sub>) 1.63–4.62 μM). Moreover, (<i>E</i>)-3-(8-(<i>tert</i>-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-<i>N</i>-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (<b>6bd</b>) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, <b>6bd</b> could cross the blood–brain barrier in vitro. More importantly, compared to edaravone, <b>6bd</b> had stronger free-radical scavenging activity. Molecular docking studies revealed that <b>6bd</b> could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate <b>6bd</b> as a leading structure worthy of further investigation.https://www.mdpi.com/1420-3049/26/5/1303Alzheimer’s diseaseClaulansine F–donepezil hybridsAChE inhibitory activityfree-radical scavenging activityneuroprotective effects |
| spellingShingle | Yingda Zang Ke Liu Weiping Wang Chuangjun Li Jie Ma Jingzhi Yang Xinyi Chen Xiaoliang Wang Dongming Zhang Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities Molecules Alzheimer’s disease Claulansine F–donepezil hybrids AChE inhibitory activity free-radical scavenging activity neuroprotective effects |
| title | Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities |
| title_full | Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities |
| title_fullStr | Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities |
| title_full_unstemmed | Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities |
| title_short | Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities |
| title_sort | claulansine f donepezil hybrids as anti alzheimer s disease agents with cholinergic free radical scavenging and neuroprotective activities |
| topic | Alzheimer’s disease Claulansine F–donepezil hybrids AChE inhibitory activity free-radical scavenging activity neuroprotective effects |
| url | https://www.mdpi.com/1420-3049/26/5/1303 |
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