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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2015 Jul 16

PMID 26177091

Citations 49

Authors

Wenhua Chu

Dong Zhou

Vrinda Gaba

Jialu Liu

Shihong Li

Xin Peng

Jinbin Xu

Dhruva Dhavale

Devika P Bagchi

Andre Davignon

Naomi B Shakerdge

Brian J Bacskai

Zhude Tu

Paul T Kotzbauer

Robert H Mach

Affiliations

Soon will be listed here.

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.

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