Recently, histone deacetylase 6 (HDAC6) has attracted considerable attention for its potential in treating neurodegenerative disorders. In this paper, a series of tetrahydroisoquinoline derivatives were designed and synthesized as selective HDAC6 inhibitors. 4-((7-chloro-3, 4-dihydroisoquinolin-2(1H)-yl)methyl)-3-fluoro-N-hydroxybenzamide (8g), the most promising compound, potently inhibited HDAC6 (IC50 = 7.0 nM) and exhibited >2000 ~ fold selectivity over HDAC1. Molecular simulation indicated its molecular basis of HDAC6 inhibition. In vitro, 8g showed no significant toxicity on rat dopaminergic pheochromocytoma PC-12 cells. Furthermore, we demonstrated that 8g induced neurite outgrowth and showed good neuroprotective activity in PC-12 cells. Our research provided a new promising structure for the development of HDAC6is against Alzheimer's disease.
