Referenced in: none

Automatically associated channels: Kv11.1

Title: Novel 1-phenyl-3-hydroxy-4-pyridinone derivatives as Multifunctional Agents for the therapy of Alzheimer's Disease.

Authors: Rong Sheng, Li Tang, Liu Jiang, LIngjuan Hong, Ying Shi, Naiming Zhou, Yong-Zhou Hu

Journal, date & volume: ACS Chem Neurosci, 2015 Oct 19 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26479744

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.