title: Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer's disease.
abstract: Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimer's disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1's enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. michela.rosini@unibo.it
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
authors.forename: Elena
authors.initials: E
authors.lastname: Simoni
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Matera
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002091:Butyrylcholinesterase / Q000378:metabolism; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D008063:Thioctic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D008024:Ligands; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D008063:Thioctic Acid; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase