title: DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimer's therapy.
abstract: Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, compounds 9a-d exhibited good inhibition of self-induced Aβ1-42aggregation with inhibition ratio 57.7-71.5%. For MAO, these new hybrids exhibited good balance of inhibition for MAO-A and MAO-B. In addition, all target compounds retained the antioxidant activity of edaravone, showed equal or better antioxidant activity than edaravone. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compounds 9a-d would be able to cross the blood-brain barrier and reach their biological targets in the central nervous system. The promising results in all assays demonstrated that the strategy behind the designing of compounds was rational and favourable. Taken together, these preliminary findings suggested that the compounds with the strongest bioactivity deserves further investigated for pharmacological development in AD therapy.
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: 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: Xia
authors.initials: X
authors.lastname: Yang
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: Li
authors.initials: L
authors.lastname: Luo
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: Rui
authors.initials: R
authors.lastname: Xu
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: Yunxiaozhu
authors.initials: Y
authors.lastname: Zheng
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: Zhongcheng
authors.initials: Z
authors.lastname: Cao
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: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000737:chemistry; D001572:Benzofurans / Q000737:chemistry*; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D000077553:Edaravone; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001572:Benzofurans; D008996:Monoamine Oxidase Inhibitors; C027125:3-n-butylphthalide; D008995:Monoamine Oxidase; D000077553:Edaravone; D000983:Antipyrine
keywords: Alzheimer’s disease; Antioxidant; Aβ aggregation inhibitors; DL-NBP-Edaravone hybrids; MAO inhibitors