Abstract: In this study, a series of 18 histone deacetylases inhibitors (HDACis), derived from our in-house anti-cancer trans-β-arylacryl 1, 2, 3, 4-tetrahydroisoquinoline-based scaffold, were designed, synthesized, and antitumor evaluated. HDAC1 inhibitory activity assay showed that compounds 13d-13f and 13m-13o demonstrated attractive enzymatic activity with IC₅₀ at single-digit nanomolar or subnanomolar level.In addition, 13o exerted superior anti-proliferative activity (A549, IC₅₀ = 0.89 μmol·L^-1; HCT116, IC₅₀ = 0.49 μmol·L^-1) to that of vorinostat (SAHA).Besides, 13e, with the most potent HDAC1 enzymatic activity (IC₅₀ = 3.8 nmol·L^-1), also displayed attractive cellular activity (A549, IC₅₀ = 1.74 μmol·L^-1; HCT116, IC₅₀ = 2.43 μmol·L^-1). The Western blot analysis illustrated that 13e treatment increased the acetylation of H3 and α-tubulin in a dose-dependent manner in A549 cells. In summary, 13e and 13o deserve further functional investigation.