Synthesis, anti-tumor evaluation, and mechanistic investigation of 3-indolylpyrazole phenoxyacetamide derivatives against chronic myeloid leukemia cells

Both indole and phenol structures are important active components of drug structure. In this study, a series of novel 3-indole pyrazole derivatives incorporating phenolic moieties were rationally designed and synthesized through molecular hybridization strategy. A comprehensive evaluation of antitumor activity demonstrated that these target compounds exhibited remarkable cytotoxicity across four distinct cancer cell lines. Notably, compound O11 emerged as the most potent compound, showing exceptional activity against human chronic myeloid leukemia (K562) cells with an IC50 value of 2.64 μM. The investigation into the mechanism of transcription and protein validation revealed that the anti-tumor effects were produced through multiple pathways: potential interference with the mitochondrial membrane, modulated the intracellular levels of reactive oxygen species, inhibited the activation of the NF-κB signaling pathway, blockade of the cell cycle at the G2/M phase, and ultimately, apoptosis of the K562 cells. These findings underscore the potential of O11, a promising compound that offers new possibilities for the further development of cancer therapeutics. In this study, 22 novel 3-indolylpyrazole phenoxyacetamide derivatives were synthesized. Among them, compound O11 (IC50 = 2.6 μM) was identified as having excellent anti-proliferative activity against K562 cels. Mechanistic studies revealed that O11 exerted its antitumor effects by modulating intracellular ROS levels, mitochondrial membrane potential, and inhibiting the activation of NF-κB.