title: Design, synthesis, and evaluation of 2-piperidone derivatives for the inhibition of β-amyloid aggregation and inflammation mediated neurotoxicity.
abstract: A series of novel multipotent 2-piperidone derivatives were designed, synthesized and biologically evaluated as chemical agents for the treatment of Alzheimer's disease (AD). The results showed that most of the target compounds displayed significant potency to inhibit Aβ(1-42) self-aggregation. Among them, compound 7q exhibited the best inhibition of Aβ(1-42) self-aggregation (59.11% at 20 μM) in a concentration-dependent manner. Additionally, the compounds 6b, 7p and 7q as representatives were found to present anti-inflammation properties in lipopolysaccharide (LPS)-induced microglial BV-2 cells. They could effectively suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. Meanwhile, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity. The molecular modeling studies demonstrated that compounds matched the pharmacophore well and had good predicted physicochemical properties and estimated IC50 values. Moreover, compound 7q exerted a good binding to the active site of myeloid differentiation factor 88 (MyD88) through the docking analysis and could interfere with its homodimerization or heterodimerization. Consequently, these compounds emerged as promising candidates for further development of novel multifunctional agents for AD treatment.
authors.affiliation: Department of Medicinal Chemistry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: fengchao@mails.tjmu.edu.cn.
authors.forename: Feng-Chao
authors.initials: FC
authors.lastname: Jiang
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D010881:Piperidones; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); C043384:2-piperidone
keywords: 2-Piperidone derivatives; Alzheimer’s disease; Molecular docking; Neuroinflammation; Neuroprotection; β-Amyloid aggregation