title: Tacrine-based Multifunctional Agents in Alzheimer's Disease: An Old Story in Continuous Development§.
abstract: BACKGROUND
  The design of multifunctional agents represents one of the most active research field in medicinal chemistry. In particular, tacrine, a well known Acetylcholinesterase inhibitor, is one of the most used starting point to develop multifunctional ligands and hundreds of papers report about these new agents. This is the third review of a series concerning tacrinebased multifunctional ligands; in particular, in the present, we will summarize and discuss the most intriguing examples of tacrine-based multifunctional agents published since 2013 until 2016.
  
  
  METHODS
  We analyzed the bibliographic databases for peer-reviewed publications concerning tacrine-based multifunctional agents possessing biological actions that go beyond the simple "cholinergic" blockage. These papers have been subdivided according to their biological activities. Since this is the third review of a series, we took into considerations only the papers appeared since 2013 until 2016.
  
  
  RESULTS
  In this review, we have analyzed more than 33 papers. All the reported compounds retain good inhibitory activity towards acetyl- and butyryl-cholinesterase. The other biological activities concern mostly inhibition of a) β-amyloid aggregation, b) β-secretase, c) monoamino oxidases, modulation of τ and ROS and metal chelation.
  
  
  CONCLUSIONS
  The analysis of the current literature reported in this review confirm the importance of tacrine as scaffold to develop multifunctional agents potentially usefull to contrast Alzheimer's disease. Furthermore, the compounds herein reported showed very intriguing biological activities that could be used as starting point to develop new compounds even more interesting and, hopefully, clinically usefull to contrast Alzheimer's Disease.
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ticchi
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Huan H
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Nibal
authors.initials: N
authors.lastname: Betari
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d'Augusto 237, 47921 Rimini. Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D017382:Reactive Oxygen Species / Q000378:metabolism; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D008024:Ligands; D017382:Reactive Oxygen Species; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Neurodegenerative diseases; acetylcholinesterase inhibitors; dual binding acetylcholinesterase inhibitors; tacrine; tacrine hybrids