title: Multifunctional scutellarin-rivastigmine hybrids with cholinergic, antioxidant, biometal chelating and neuroprotective properties for the treatment of Alzheimer's disease.
abstract: To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed ligand strategy. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metal-chelating properties and neuroprotective effects against hydrogen peroxide induced PC12 cell injury were evaluated in vitro. The results showed that most of the synthetic compounds exhibited good multifunctional activities. In particular, compound 15c exhibited dual inhibitory potency on acetylcholinesterase and butyrylcholinesterase with IC50 values of 0.57 and 22.6μM, respectively, and good antioxidative activity, with a value 1.3-fold of Trolox. In addition, 15c acted as a selective biometal chelator and possessed neuroprotective effects. Furthermore, 15c could cross the blood-brain barrier (BBB) in vitro and had significant neuroprotective effects in scopolamine-induced cognitive impairment in mice. Taken together, these results suggest that compound 15c might be a potential multifunctional agent for the treatment of AD.
authors.affiliation: 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.
authors.forename: Zhipei
authors.initials: Z
authors.lastname: Sang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Qiang
authors.affiliation: 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.
authors.forename: Ganyuan
authors.initials: G
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute of Traditional Chinese Medicine Pharmacology and Toxicology, Sichuan Academy of Chinese Medicine Sciences, Chengdu 610041, China. Electronic address: tanzhh616@163.com.
authors.forename: Zhenghuai
authors.initials: Z
authors.lastname: Tan
authors.affiliation: 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. Electronic address: dengyong@scu.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047310:Apigenin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D005965:Glucuronates / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats
chemical_list: D000975:Antioxidants; D002219:Carbamates; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D005965:Glucuronates; D018696:Neuroprotective Agents; C484876:scutellarin; D047310:Apigenin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Antioxidant activity; Cholinesterase inhibitors; Metal-chelating agents; Neuroprotective effects; Scutellarein carbamate derivatives