Synthesis and evaluation of selegiline derivatives as monoamine oxidase inhibitor, antioxidant and metal chelator against Alzheimer's disease.
A series of compounds with monoamine oxidase inhibition and biometal chelation activities were designed, synthesised and evaluated as agents against Alzheimer's disease. The in vitro assay shows that most target compounds exhibit good MAO-B activities with submicromolar IC50 values and antioxidant activity (1.49-5.67 ORAC-FL values). The selected compounds were used to determine the biometal chelating ability using UV-vis spectrometry and high-resolution mass spectrometry, which confirm that they can effectively interact with copper(II), iron(II) and zinc(II). The ThT fluorescence binding assay indicates that the synthetic compounds can inhibit Cu(II)-induced Aβ1-42 aggregation. The parallel artificial membrane permeation assay shows that most target compounds can cross the BBB. Based on these results, compound 8a was selected as a potential multifunctional agent for the treatment of AD.
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Shishun
S
Xie
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Jie
J
Chen
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Xiruo
X
Li
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Tao
T
Su
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Yali
Y
Wang
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Zhiren
Z
Wang
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: huangl72@mail.sysu.edu.cn.
Ling
L
Huang
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lixsh@mail.sysu.edu.cn.
Xingshu
X
Li
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D002413:Cations, Divalent; D002463:Cell Membrane Permeability; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry; D008567:Membranes, Artificial; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry; D066329:Protein Aggregates / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D012642:Selegiline / Q000138:chemical synthesis* / Q000494:pharmacology; D012996:Solutions; D015032:Zinc / Q000737:chemistry
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002413:Cations, Divalent; D002614:Chelating Agents; D008567:Membranes, Artificial; D008996:Monoamine Oxidase Inhibitors; D010446:Peptide Fragments; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D012996:Solutions; C075222:amyloid beta-protein (1-42); D012642:Selegiline; D003300:Copper; D007501:Iron; D008995:Monoamine Oxidase; D015032:Zinc
Alzheimer’s disease; Metal chelator; Monoamine oxidase inhibitor