LAUSR

&NA; Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (A&bgr;) protein. Starting from previous findings in the antiaggregating activity of a class of indolin‐2‐ones inhibiting A&bgr; fibrillization, 5‐methoxyisatin 3‐(4‐isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of A&bgr; aggregation and cholinesterases with IC50s in the low &mgr;M range. With the aim of increasing aqueous solubility, a Mannich‐base functionalization led to the synthesis of N‐methylpiperazine derivative 2. At acidic pH, an outstanding solubility increase of 2 over the parent compound 1 was proved through a turbidimetric method. HPLC analysis revealed an improved stability of the Mannich base 2 at pH 2 along with a rapid release of 1 in human serum as well as an outstanding hydrolytic stability of the parent hydrazone. Coincubation of A&bgr;1–42 with 2 resulted in the accumulation of low MW oligomers, as detected with PICUP assay. Cell assays on SH‐SY5Y cells revealed that 2 exerts strong cytoprotective effects in both cell viability and radical quenching assays, mainly related to its active metabolite 1. These findings show that 2 drives the formation of non‐toxic, off‐pathway A&bgr; oligomers unable to trigger the amyloid cascade and toxicity. Graphical abstract Figure. No caption available.