title: Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity.
abstract: Memoquin (1) is a lead compound multitargeted against Alzheimer's disease (AD). It is an AChE inhibitor, free-radical scavenger, and inhibitor of amyloid-β (Aβ) aggregation. A new series of 1 derivatives was designed and synthesized by linking its 2,5-diamino-benzoquinone core with motifs that are present in the structure of known amyloid binding agents like curcumin, the benzofuran derivative SKF64346, or the benzothiazole bearing compounds KHG21834 and BTA-1. The weaker AChE inhibitory potencies and the concomitant nearly equipotent anti-amyloid activities of the new compounds with respect to 1 resulted in a more balanced biological profile against both targets. Selected compounds turned out to be effective Aβ aggregation inhibitors in a cell-based assay. By properly combining two or more distinct pharmacological properties in a molecule, we can achieve greater effectiveness compared to single-targeted drugs for investigating AD.
authors.affiliation: Department of Pharmaceutical Sciences-Alma Mater Studiorum-Bologna University, Via Belmeloro 6, 40126 Bologna, Italy. marialaura.bolognesi@unibo.it
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.forename: Fabiana
authors.initials: F
authors.lastname: Morroni
authors.forename: Federica
authors.initials: F
authors.lastname: Lizzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000473:Alkanes / Q000737:chemistry* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005021:Ethylamines / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure
chemical_list: D000473:Alkanes; D000682:Amyloid; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D005021:Ethylamines; C521476:memoquin