Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities.

[Display omitted] • Potent and selective HDAC6 inhibitors based on the Tetrahydro- β -carboline scaffold. • Computational simulations suggested the key interactions between representative 11d and HDAC6. • 11d exhibited promising neurite outgrowth-promoting activity and neuroprotective activity. Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro- β -carboline (TH β C) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC 50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC 50 , 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner. In vitro, 11d induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of H 2 O 2 -induced oxidative stress. [ABSTRACT FROM AUTHOR]