Design, synthesis and biological evaluation of indane-2-arylhydrazinylmethylene-1,3-diones and indol-2-aryldiazenylmethylene-3-ones as beta-amyloid aggregation inhibitors.
Biological screening of (hetero)aromatic compounds allowed the identification of some novel inhibitors of Abeta(1-40) aggregation, bearing indane and indole rings as common scaffolds. Molecular decoration of lead compounds led to inhibitors exhibiting a potency, measured by the Thioflavin T fluorimetric assay, ranging from high to low micromolar IC(50). The 2-(p-isopropylphenyldiazenylmethylene)indolone derivative 6c resulted as the most potent aggregation inhibitor exhibiting an IC(50) of 1.4 muM, with complete lack of fibril formation as confirmed by transmission electron microscopy. Structure-activity relationships suggested that binding to the Abeta peptide may be largely guided by pi-stacking and hydrogen bond interactions.
Dipartimento Farmacochimico, Università degli studi di Bari Aldo Moro, via Orabona 4, 70125 Bari, Italy.
Marco
M
Catto
Rosaria
R
Aliano
Angelo
A
Carotti
Saverio
S
Cellamare
Fausta
F
Palluotto
Rosa
R
Purgatorio
Angelo
A
De Stradis
Francesco
F
Campagna
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D052160:Benzothiazoles; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D007211:Indoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T