Discovery of a Novel 4,5-Dihydro-1H-pyrazole-1-carbothioamide Derivative with Cytotoxic, Apoptotic, and ABL1 Inhibitory Activities Against Chronic Myeloid Leukemia

Background/Objectives: Chronic myeloid leukemia (CML) is a hematological malignancy driven by the constitutively active BCR-ABL1 fusion protein. Although current ABL1 tyrosine kinase inhibitors (TKIs) have improved CML management, resistance remains a major challenge, highlighting the need for novel therapeutic strategies. Methods: A chalcone derivative containing naphthalene and toluene moieties (A) was synthesized from 2-acetonaphthone and p-tolualdehyde and subsequently converted into a novel 4,5-dihydro-1H-pyrazole-1-carbothioamide derivative (B) through reaction with thiosemicarbazide. The cytotoxicity of compounds A and B against K562 CML cells was evaluated using the MTT assay. The active compound was further investigated for cytotoxic selectivity using HL-60 acute myeloid leukemia (AML) cells and healthy PBMCs. Apoptotic effects in K562 cells were analyzed using Annexin V/ethidium homodimer staining, whereas ABL1 inhibitory activity was determined using the ADP-Glo kinase assay. The potential interaction between the active compound and ABL1 was assessed by molecular docking analysis. Results: Compound B displayed potent cytotoxic activity against K562 cells with an IC50 value of 6.92 ± 1.14 µM and demonstrated selectivity toward leukemic cells over PBMCs (SI = 5.4). Treatment with compound B markedly induced apoptosis in K562 cells. In addition, compound B inhibited ABL1 activity in a concentration-dependent manner. Molecular docking studies revealed a favorable binding orientation within the ATP-binding pocket of ABL1. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) analysis predicted favorable pharmacokinetic properties for compound B. Conclusions: These findings demonstrate that compound B possesses cytotoxic, pro-apoptotic, and ABL1 inhibitory activities against CML cells and may serve as a promising lead structure for the development of novel therapeutic agents targeting CML.