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

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 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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