Design,synthesis and evaluation of novel 7-aminoalkyl-substituted flavonoid derivatives with improved cholinesterase inhibitory activities |
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| Institution: | 1. Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, People’s Republic of China;2. Institute of Chemical Biology, Henan University, Kaifeng 475004, People’s Republic of China;1. Department of Chemistry, University of Pune, Pune 411007, India;2. MPI für Chemische Energiekonversion, Stiftstr. 34-36, 45470 Müllheim an der Ruhr, Germany;3. Center for Material Characterization, National Chemical Laboratory, Pune 411008, India;4. School of Biological Sciences, National Institute of Science Education and Research (NISER), Bhubaneswar 751005, India;1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India;2. Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India;1. Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany;2. Medical Mission Institute, Hermann-Schell-Strasse 7, 97074 Würzburg, Germany;3. Institute for Pharmacy and Biochemistry, Johannes-Gutenberg-University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany;4. Institute for Molecular Infection Biology, Julius-Maximilians-University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany;5. Biochemistry Center (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany;1. Department of Chemistry, Inorganic Chemistry Division, Istanbul University, 34320 Avcilar, Istanbul, Turkey;2. Department of Chemistry, Analytical Chemistry Division, Istanbul University, 34320 Avcilar, Istanbul, Turkey;1. Department of Chemistry, University of Washington, Seattle, WA 98195, USA;2. Department of Medicine, University of Washington, Seattle, WA 98195, USA;3. Department of Biochemistry, University of Washington, Seattle, WA 98195, USA;4. Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN, USA;1. College of Life Sciences, Shenzhen University, Shenzhen 518060, China;2. Department of Pharmacy, School of Medicine, Shenzhen University, No. 3688, Nanhai Road, Nanshan, Shenzhen 518060, China;3. School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China;4. Key Laboratory of Structural Biology, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, China |
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| Abstract: | A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64 μM for AChE and 0.42 μM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a–5r) did not affect PC12 and HepG2 cell viability at the concentration of 10 μM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer’s disease. |
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| Keywords: | Flavonoid derivatives Cholinesterase Anti-Alzheimer agent Molecular modeling Cytotoxicity |
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