title: Targeting Alzheimer's disease: Novel indanone hybrids bearing a pharmacophoric fragment of AP2238.
abstract: We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizzo
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Luisa
authors.initials: L
authors.lastname: Ceccarini
authors.forename: Lorna
authors.initials: L
authors.lastname: Piazzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Gobbi
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Angela
authors.initials: A
authors.lastname: Rampa
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D001761:Bleomycin; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D003198:Computer Simulation; D003374:Coumarins / Q000737:chemistry* / Q000627:therapeutic use; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000737:chemistry* / Q000627:therapeutic use; D008130:Lomustine; D008727:Methotrexate; D010446:Peptide Fragments / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: C513133:1,4-bis(4-aminostyryl)-2-methoxybenzene; C549965:2-(4-((benzylmethylamino)methyl)benzylidene)-6-(5-diethylaminopentyloxy)-3,4-dihydro-2H-naphthalen-1-one; C549966:2-(4-((benzylmethylamino)methyl)benzylidene)-6-(5-piperidin-1-yl-pentyloxy)-3,4-dihydro-2H-naphthalen-1-one; C475423:AP 2238; D016229:Amyloid beta-Peptides; D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D003374:Coumarins; D007189:Indans; D010446:Peptide Fragments; D010880:Piperidines; D011994:Recombinant Proteins; D013267:Stilbenes; D013764:Tetrahydronaphthalenes; C075222:amyloid beta-protein (1-42); D001761:Bleomycin; D008130:Lomustine; D000077265:Donepezil; C013352:indacrinone; D000110:Acetylcholinesterase; D008727:Methotrexate