title: Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties.
abstract: Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional 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: 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: Xiao-Bing
authors: XB
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: Ge
authors: G
authors: Dong
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.
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: Ping-Ping
authors: PP
authors: Guo
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: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002839:Chromans / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016716:PC12 Cells; D010851:Picrates / Q000737:chemistry; D051381:Rats; D013552:Swine; D013619:Tacrine / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001713:Biphenyl Compounds; D002800:Cholinesterase Inhibitors; D002839:Chromans; D018696:Neuroprotective Agents; D010851:Picrates; D013619:Tacrine; C004931:1,1-diphenyl-2-picrylhydrazyl; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: Alzheimer's disease; Antioxidant; Cholinesterase; Hepatotoxicity; Tacrine; Trolox