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 IC₅₀ 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.