From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders
A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (C...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1036030/full |
| _version_ | 1811187038783799296 |
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| author | Junbo Wu Junbo Wu Honghua Zhang Yuying Wang Gaofeng Yin Qien Li Linsheng Zhuo Hongjin Chen Zhen Wang Zhen Wang |
| author_facet | Junbo Wu Junbo Wu Honghua Zhang Yuying Wang Gaofeng Yin Qien Li Linsheng Zhuo Hongjin Chen Zhen Wang Zhen Wang |
| author_sort | Junbo Wu |
| collection | DOAJ |
| description | A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H2O2-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs. |
| first_indexed | 2024-04-11T13:56:27Z |
| format | Article |
| id | doaj.art-e0f9b6e8e19c44e1a7be95dc935740c8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T13:56:27Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e0f9b6e8e19c44e1a7be95dc935740c82022-12-22T04:20:21ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.10360301036030From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disordersJunbo Wu0Junbo Wu1Honghua Zhang2Yuying Wang3Gaofeng Yin4Qien Li5Linsheng Zhuo6Hongjin Chen7Zhen Wang8Zhen Wang9Department of Colorectal Surgery, The Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaSchool of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaSchool of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaState Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, ChinaSchool of Pharmacy, Lanzhou University, Lanzhou, ChinaTibetan Medical College, Qinghai University, Xining, Qinghai, ChinaSchool of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaDepartment of Colorectal Surgery, The Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaSchool of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, ChinaDepartment of Colorectal Surgery, The Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaA novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H2O2-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.https://www.frontiersin.org/articles/10.3389/fphar.2022.1036030/fullcarbamylated tryptamine derivativesbenzylationpromising building blocksMTDLscholinesterase inhibitorsneuroprotection |
| spellingShingle | Junbo Wu Junbo Wu Honghua Zhang Yuying Wang Gaofeng Yin Qien Li Linsheng Zhuo Hongjin Chen Zhen Wang Zhen Wang From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders Frontiers in Pharmacology carbamylated tryptamine derivatives benzylation promising building blocks MTDLs cholinesterase inhibitors neuroprotection |
| title | From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders |
| title_full | From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders |
| title_fullStr | From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders |
| title_full_unstemmed | From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders |
| title_short | From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders |
| title_sort | from tryptamine to the discovery of efficient multi target directed ligands against cholinesterase associated neurodegenerative disorders |
| topic | carbamylated tryptamine derivatives benzylation promising building blocks MTDLs cholinesterase inhibitors neuroprotection |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1036030/full |
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