Design, Synthesis, and Antihematological Tumor Activity of Dihydroartemisinin–Loxoprofen Hybrids

In this study, seven novel dihydroartemisinin–loxoprofen hybrids are designed and synthesized, which exhibits significantly enhanced anticancer activity compared to their parent compounds. Through antiproliferation assays, compound 5 is identified as the most potent agent, showing remarkable efficacy against acute myeloid leukemia (AML) cell lines, with IC 50 values of 0.013 μM for HL‐60 cell, 0.048 μM for U937 cell, and 0.010 μM for THP‐1 cell. The antitumor activity of compound 5 is more than tenfold higher than that of the parent compounds. Furthermore, fluorescence microscopy and flow cytometry analyses reveal that compound 5 induces apoptosis in HL‐60 cells more effectively than the positive drug cytarabine. X‐ray single‐crystal diffraction analysis confirms the absolute configuration of these compounds. Molecular docking studies demonstrate strong binding affinities between all seven hybrid molecules and COX‐2 (PDB ID: 5IKR) via hydrophobic interactions, hydrogen bonds, and π –π stacking with key residues. Evaluations in human normal liver THLE‐2 cells show favorable selectivity indices (SI > 10), and in silico absorption, distribution, metabolism, and excretion (ADME) predictions indicate high gastrointestinal absorption, CYP3A4‐mediated metabolism, and bioavailability of 8.15–9.36%. The results highlight the potential of dihydroartemisinin–loxoprofen hybrids as a promising research direction for AML treatment strategies.