Discovery of Potent HDAC6-Selective Inhibitors Based on Artemisinin: Design, Synthesis, and Antitumor Evaluation

Beyond their well-established antimalarial effects, artemisinin and its derivatives have demonstrated promising antitumor activity. Herein, a series of novel artemisinin-based histone deacetylase inhibitors were rationally designed and synthesized using a pharmacophore hybridization strategy. Among them, compound G25 exhibited the most potent in vitro antiproliferative activity, particularly against hematologic malignancies, including MV4–11 (IC₅₀ = 28 nM), MOLM-13 (IC₅₀ = 89 nM), and HL60 cells (IC₅₀ = 92 nM). Mechanism studies revealed that G25 induced autophagy and apoptosis in a p53-dependent manner. HDAC isoform profiling demonstrated that G25 was a potent and selective HDAC6 inhibitor (IC₅₀ = 12 nM). Importantly, G25 showed in vivo antileukemic activity in a MOLM-13-Luc acute myeloid leukemia xenograft model, as evidenced by suppressed tumor progression and a trend toward prolonged survival. Pharmacokinetic evaluation indicated rapid metabolic clearance, suggesting the need for further optimization. Collectively, G25 represents a promising lead scaffold for developing artemisinin-derived HDAC6-selective antitumor agents.