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

Wenhua Chu, Dong Zhou, Vrinda Gaba, Jialu Liu, Shihong Li, Xin Peng, Jinbin Xu, Dhruva Dhavale, Devika P. Bagchi, André D'Avignon, Naomi B. Shakerdge, Brian J. Bacskai, Zhude Tu, Paul T. Kotzbauer, Robert H. Mach

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)6002-6017
Number of pages16
JournalJournal of Medicinal Chemistry
Volume58
Issue number15
DOIs
StatePublished - Jul 15 2015

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