Novel salicylamide derivatives as potent multifunctional agents for the treatment of Alzheimer's disease: Design,synthesis and biological evaluation |
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| Affiliation: | 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. School of Pharmacy, Anhui Medical University, Hefei, 230032, China;2. The Central Hospital of Wuhan, Tongji Medical College of HUST, Wuhan, 430000, China;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. Experiment Center of Teaching & Learning, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;2. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;3. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China;1. Department of Medicinal Chemistry, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;2. College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China;1. College of Life Sciences, Xinyang Normal University, Xinyang, Henan, China;2. School of Geographic Sciences, Xinyang Normal University, Xinyang, Henan, China;3. Shaanxi Key Laboratory of Natural Products & Chemical Biology, School of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, Shaanxi Province, China |
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| Abstract: | A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced Aβ1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward RatAChE and EeAChE with IC50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced Aβ1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced Aβ1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment. |
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| Keywords: | Alzheimer’s disease Salicylamide derivatives Acetylcholinesterase inhibitors Antioxidant Anti-neuroinflammatory agents |
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