Design,synthesis and evaluation of a novel metal chelator as multifunctional agents for the treatment of Alzheimer’s disease |
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| Institution: | 1. School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, PR China;2. Department of Medicinal Chemistry and the Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN 55414, USA;3. School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China;4. Suzhou Key Laboratory of Biomaterials and Technologies & Collaborative Innovation Center of Suzhou Nano Science and Technology, Suzhou 215123, PR China;1. Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, 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;1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;2. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran;3. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran;4. Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;5. Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran;6. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;8. Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;2. Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon;3. Noha Gouda, Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt;1. University of Chemistry and Technology, Technická 5, 16628 Prague 6, Czech Republic;2. First Faculty of Medicine-BIOCEV, Charles University, Kateřinská 32, 12108 Prague 2, Czech Republic;3. Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 81101 Bratislava, Slovakia;1. Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland;3. Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;4. Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland;1. School of Pharmacy, Anhui Medical University, Hefei, 230032, China;2. The Central Hospital of Wuhan, Tongji Medical College of HUST, Wuhan, 430000, China |
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| Abstract: | A series of compounds following the lead compounds including deferasirox and tacrine were designed, synthesized and evaluated as multifunctional agents against Alzheimer’s disease (AD). In vitro studies showed that most synthesized compounds exhibited good multifunctional activities in inhibiting acetylcholinesterase (bAChE), and chelating metal ions. Especially, compound TDe demonstrated significant metal chelating property, a moderate acetylcholinesterase (AChE) inhibitory activity and an antioxidant activity. Results from the molecular modeling indicated that TD compounds were mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of TcAChE. Moreover, TDe showed a low cytotoxicity but a good protective activity against the injury caused by H2O2. These results suggest that TD compounds might be considered as attractive multi-target cholinesterase inhibitor and will play important roles in the treatment of AD. |
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| Keywords: | Alzheimer's disease Multifunctional agents Acetylcholinesterase inhibitors Metal chelator Tacrine Deferasirox |
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