title: Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease.
abstract: A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 μM). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Sai-Sai
authors: SS
authors: Xie
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Xiaobing
authors: X
authors: Wang
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Neng
authors: N
authors: Jiang
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Wenying
authors: W
authors: Yu
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Kelvin D G
authors: KD
authors: Wang
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Jin-Shuai
authors: JS
authors: Lan
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
authors: Zhong-Rui
authors: ZR
authors: Li
authors: State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
authors: Ling-Yi
authors: LY
authors: Kong
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy*; D001578:Benzopyrans / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry*; D015195:Drug Design; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D013619:Tacrine / Q000737:chemistry*
chemical_list: C000604755:3,4-dimethyl-7-(2-(4-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperazin-1-yl)ethoxy)-2H-chromen-2-one; D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D010879:Piperazines; D013619:Tacrine; C030123:coumarin; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase
keywords: Alzheimer's disease; Cholinesterase; Coumarin; Docking; Monoamine oxidase; Tacrine