title: Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property.
abstract: Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Aβ42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Aβ aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer's disease.
authors.affiliation: Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Zhikun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China. Electronic address: lei.fang@seu.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gou
authors.affiliation: Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: chenliduo12@gmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003474:Curcumin / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D013619:Tacrine; D003474:Curcumin
keywords: Alzheimer’s disease; Cholinesterase inhibitors; Metal ions-chelating ability; Neuroprotective property; Tacrine-curcumin hybrids