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 (THβC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC50, 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 H2O2-induced oxidative stress.