title: Discovery of indanone derivatives as multi-target-directed ligands against Alzheimer's disease.
abstract: A series of indanone derivatives were designed, synthesized, and tested using a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations assessed the activities of the agents for the inhibition of cholinesterases (AChE and BuChE), the inhibition of amyloid beta (Aβ) self-assembly, and the catalysis of the disassembly of preformed Aβ oligomers and measured their antioxidant activities. Our results demonstrate that most of the synthesized compounds demonstrated good inhibitory activity against AChE with IC50 values in the nanomolar range. In particular, compounds 9 (IC50 = 14.8 nM) and 14 (IC50 = 18.6 nM) exhibited markedly higher inhibitory activities than tacrine and similar activities to donepezil. In addition, 9 and 14 significantly inhibited Aβ aggregation (inhibition rates of 85.5% and 83.8%, respectively), catalysed the disaggregation of Aβ fibrils generated by self-induced Aβ aggregation, and exhibited antioxidant activity. Furthermore, these two compounds can cross the blood-brain barrier (BBB) in vitro. These properties highlight the potential of these new compounds to be developed as multi-functional drugs for the treatment of Alzheimer's disease.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Fanchao
authors.initials: F
authors.lastname: Meng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lixsh@mail.sysu.edu.cn.
authors.forename: Xingshu
authors.initials: X
authors.lastname: Li
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry; D010539:Permeability; D066329:Protein Aggregates / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D007189:Indans; D008024:Ligands; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); C013352:indacrinone; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase inhibitors; Alzheimer's disease; Amyloid beta; Antioxidant; Indanone derivatives