title: Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer's disease therapy.
abstract: A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MTDLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC50 value of 0.097μM, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a, 6a and 6e demonstrated inhibitory activity against Aβ self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7) also showed potent ABTS(+) scavenging and moderate copper ion chelating activity in vitro.
authors.affiliation: School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Peng
authors.affiliation: School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medicine, Zhejiang University, Hangzhou 310006, China.
authors.forename: Yunzhen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: shengr@zju.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Sheng
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D048448:Phenylcarbamates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000068836:Rivastigmine; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D048448:Phenylcarbamates; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D003474:Curcumin; D000068836:Rivastigmine
keywords: AChE/BuChE inhibitor; Aβ self-aggregation inhibitor; Metal chelator; Multitarget-directed ligands; Radical scavenger