title: Novel 1-Phenyl-3-hydroxy-4-pyridinone Derivatives as Multifunctional Agents for the Therapy of Alzheimer's Disease.
abstract: A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H3 receptor antagonists. Most of these new compounds displayed designed quadruple functions, H3 receptor antagonism, Aβ aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC50 values in H3 receptor antagonism with high selectivity, efficient capability to interrupt the formation of Aβ(1-42) fibrils, good copper and iron chelating properties, and more potent 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS(•+)) scavenging activity than Trolox. Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood-brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Jiang
authors.affiliation: College of Life Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: Hong
authors.affiliation: College of Life Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: College of Life Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Naiming
authors.initials: N
authors.lastname: Zhou
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang 310058, China.
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D066263:Protein Aggregation, Pathological / Q000188:drug therapy; D011728:Pyridones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D002614:Chelating Agents; D006633:Histamine Antagonists; D011728:Pyridones; C020366:3-hydroxy-4-pyridone
keywords: Alzheimer’s disease; Aβ aggregation inhibition; H3R antagonism; Multifunctional agents; metal ion chelation; radical scavenge