Kroth, HeikoAnsaloni, AnnalisaVarisco, YvanJan, AsadSreenivasachary, NampallyRezaei-Ghaleh, NasrollahGiriens, ValérieLohmann, SophieLópez-Deber, María PilarAdolfsson, OskarPihlgren, MariaPaganetti, PaoloFroestl, WolfgangNagel-Steger, LuitgardWillbold, DieterSchrader, ThomasZweckstetter, MarkusPfeifer, AndreaLashuel, Hilal A.Muhs, Andreas2012-09-202012-09-202012-09-20201210.1074/jbc.M112.357665https://infoscience.epfl.ch/handle/20.500.14299/85581WOS:000309654200078Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity.text::journal::journal article::research article