title: Synthesis and biophysical evaluation of arylhydrazono-1H-2-indolinones as β-amyloid aggregation inhibitors.
abstract: A series of isatin-3-arylhydrazones were synthesized and evaluated in vitro as inhibitors of Aβ(1-40) aggregation using a thioflavin T fluorescence method. An exploration of the effects on Aβ(1-40) aggregation of a number of diverse substituents at phenylhydrazone group and 5,6- positions of the indolinone nucleus led us to single out some new anti-aggregating compounds with IC(50) values in the low micromolar range. The most active compounds carry methoxy- or hydroxy- substituents in the indolinone 5,6-positions and lipophilic groups such as iPr and Cl at 4'- and 3'-position, respectively, of the phenylhydrazone moiety. Two derivatives are noteworthy, namely 18 (IC(50) = 0.4 μM) and 42 (IC(50) = 1.1 μM). The in vitro effects of the highly active, water soluble, compound 42 on the temporal evolution of Aβ(1-40) fibrils formation were further investigated by circular dichroism spectroscopy, transmission electron microscopy and dynamic light scattering studies, which clearly showed that this compound delayed and lowered the amyloid fibril formation.
authors.affiliation: Dipartimento Farmaco Chimico, Università degli Studi di Bari" Aldo Moro", Via Orabona 4, 70125 Bari, Italy. campagna@farmchim.uniba.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Campagna
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Rosa
authors.initials: R
authors.lastname: Purgatorio
authors.forename: Cosimo D
authors.initials: CD
authors.lastname: Altomare
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Angelo
authors.initials: A
authors.lastname: De Stradis
authors.forename: Gerardo
authors.initials: G
authors.lastname: Palazzo
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D052160:Benzothiazoles; D002942:Circular Dichroism; D004353:Drug Evaluation, Preclinical; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D007211:Indoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T