title: Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors.
abstract: The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the validated AD targets β-secretase (BACE-1) and glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid and tau protein cascades has been identified as a promising AD therapeutic strategy. In our study, curcumin was identified as a lead compound for the simultaneous inhibition of both targets; therefore, synthetic efforts were dedicated to obtaining a small library of novel curcumin-based analogues, and a number of potent and balanced dual-target inhibitors were obtained. In particular, 2, 6, and 7 emerged as promising drug candidates endowed with neuroprotective potential and brain permeability. Notably, for some new compounds the symmetrical diketo and the β-keto-enol tautomeric forms were purposely isolated and tested in vitro, allowing us to gain insight into the key requirements for BACE-1 and GSK-3β inhibition.
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Rita Maria Concetta
authors.initials: RM
authors.lastname: Di Martino
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: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.affiliation: Istituto Italiano di Tecnologia , D3, via Morego 30, 16163 Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bisignano
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Centro de Investigaciones Biologicas, CSIC , Ramiro de Maetzu 9, 28040 Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.affiliation: Centro de Investigaciones Biologicas, CSIC , Ramiro de Maetzu 9, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Istituto Italiano di Tecnologia , D3, via Morego 30, 16163 Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.|Istituto Italiano di Tecnologia , D3, via Morego 30, 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Belluti
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003474:Curcumin / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis; D018696:Neuroprotective Agents / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D054852:Small Molecule Libraries; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D003474:Curcumin