Design,synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease |
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| Institution: | 1. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 611041, China;2. Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China;3. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, U.P., India;2. Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur 313001, Rajasthan, India;3. Department of Radiotherapy & Radiation Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP 221 005, India;4. Department of Nuclear Medicine, SGPGIMS, Raebareli Road, Lucknow 226014, UP, India;5. Department of Genetics, Louisiana State University Health Sciences Center, 1700 Tulane Avenue, New Orleans, LA 70112, USA;6. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Avenue, New Orleans, LA 70112, USA;1. Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa;2. Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa;3. Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia;1. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India;2. Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, Punjab 143005, India;1. Department of Chemistry, Fudan University, 2205 Songhu Road, Shanghai, 200438, China;2. School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong Zone, Shanghai, 201203, China;1. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China;2. Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, PR China |
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| Abstract: | A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer’s disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ1-42 aggregation inhibitory activity compared to the lead compound dl-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC50 = 2.66 nM), which was significantly better than Donepezil (IC50 = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development. |
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| Keywords: | Alzheimer’s disease Multi-target agents Acetylcholinesterase inhibitors Antioxidant |
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