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The synthesis and antileukemia evaluation of a series of dual HDAC/COX-2 inhibitors are reported. [Display omitted] • A series of dual HDAC/COX-2 inhibitors were designed and synthesized. • Compound 11 was identified as an effective agent to reduce the viability of different leukemia cell lines, particularly NALM6 cells (acute lymphoblastic leukemia cells). • Compound 11 inhibited the growth of NALM6 via cell cycle arrest and induction of apoptosis. • Compound 11 induced apoptotic cell death by activating PARP cleavage. • Compound 11 had the potential as a promising chemotherapeutic agent for acute lymphoblastic leukemia. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Here, we exploited the synergy between histone deacetylase inhibitors (HDACi) and cyclooxygenase 2 (COX-2) inhibitors by generating and testing a series of hybrid Celecoxib-HDAC inhibitors (selenium-containing analogues of Celecoxib) on ALL cells, of which compound 11 exhibited significant inducement to kill NALM6 cells with an average IC 50 of 9.95 ± 0.44 μM compared with control Celecoxib at 28.58 ± 1.44 μM and inhibited NALM6 cells growth via the inhibition of the cell cycle in G2 phase. Furthermore, compound 11 induced apoptosis by activating PARP cleavage. Taken together, compound 11 possessed the potential to be developed further as a chemotherapeutic agent for ALL. [ABSTRACT FROM AUTHOR]