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

Abstract

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.

Keywords: HDAC6 inhibitor; Neurite outgrowth; Neuroprotective; Selectivity; THβC.