Design,Synthesis And Biological Evaluation Of 5-hydroxy Pyranone Derivatives As Multitarget Agents Against Alzheimer’s Disease

Alzheimer’s disease(AD)is the most common form of dementia.The etiology of AD remains elusive and multiple factors are involved in the process of AD.The multitarget-directed ligands(MTDLs)designed for this fatal neurodegenerative disorder exhibit promising therapeutic potential.Among all the factors related with AD,the Aβ aggreagtation,metal ion dyshomeostasis,and production of reactive oxygen species(ROS)demonstrated close interaction each other.Thus,we undertook a rational pharmacophore-combination strategy to get novel 2-aryl ethylene-5-hydroxy-4-pyranone multitarget derivatives through connecting benzothiazole moiety from ThT(Aβ aggregation indicator)with 3-hydroxy-4-pyridinone from marketed metal chelator deferiprone using a vinyl linker.According to the results of biological evaluation in vitro,most of these compounds exhibited excellent Aβ1-42 aggregation inhibitory activity,efficient antioxidant activity,and potent biometals chelating properties.Moreover,the further evaluation revealed that compounds I-44 and 1-52 possesssed more favorable safety profile than HL5 and HL12.Above the datas indicate that the two compounds are promising MTDLs for AD therapy.Based on the pharmacophore of H3 receptor antagonists,the amino-propoxyphenyl moiety(H3 receptor antagonism)was incorporated into the 5-hydroxy-4-pyranone vinyl scaffold to get novel styrene derivatives.With the modification on the 5-hydroxy-4-pyranone moiety and the tertial amine group at the terminal,eighteen target compounds were obtained.The biological evaluatuion results showed that almost all of these newly designed moleculs exhibited good to excellent H3 receptor antagonistic activity,potent Aβ1-42 aggregation inhibitory activity,favourable antioxidant activity and metals chelating properties.