Design, synthesis, anticancer activity and molecular modeling of new pyrazoline derivatives as telomerase inhibitors

Telomerase is an enzyme that rebuilds chromosomal ends called telomeres, allowing cells to keep dividing. Blocking telomerase is an important strategy in cancer treatment, as tumor cells are then forced to continue dividing without repairing their telomeres, leading to progressive telomere shortening, genomic stress, and ultimately the cessation of cell division or death, thereby slowing tumor growth and enhancing the effect of chemotherapies or targeted therapies. Twelve new pyrazoline derivatives were synthesized and evaluated for their cytotoxicity against MCF-7 and MDA-MB-231 breast adenocarcinoma cells along with BJ-1 normal cells. Compounds 2c and 2g showed promising selectivity indices against both cell lines, inhibited telomerase enzymatic activity and gene expression compared to the reference standards and triggered cell cycle arrest and apoptosis. The docking study revealed that the synthesized compounds exhibited scores close to those of the co-crystallized ligand, indicating comparable binding affinities.