Design, Synthesis, and Characterization of 3‑(Benzylidene)indolin-2-one Derivatives as Ligands for α‑Synuclein Fibrils

A series
of 3-(benzylidine)­indolin-2-one derivatives were synthesized
and evaluated for their in vitro binding to alpha synuclein (α-syn),
beta amyloid (Aβ), and tau fibrils. Compounds with a single
double bond in the 3-position had only a modest affinity for α-syn
and no selectivity for α-syn versus Aβ or tau fibrils.
Homologation to the corresponding diene analogues yielded a mixture
of Z,E and E,E isomers; substitution of the indoline nitrogen with an N-benzyl group resulted in increased binding to α-syn
and reasonable selectivity for α-syn versus Aβ and tau.
Introduction of a para-nitro group into the benzene
ring of the diene enabled separation of the Z,E and E,E isomers and
led to the identification of the Z,E configuration as the more active regioisomer. The data described
here provide key structural information in the design of probes which
bind preferentially to α-syn versus Aβ or tau fibrils.