Abstract

Background: The existence of drug-resistance and lack of selectivity encourages scientists to search for novel and more selective cytotoxic agents.

Objectives: In this work, novel 1,3,4-triarylpyrazole derivatives were synthesized to study their cytotoxicity on MCF7 (human breast Cell Line). In addition, QSAR studies were performed to show the relation between the cytotoxic activity and the structural features of our new synthesized pyrazole derivatives.

Methods: Pyrazole-4-carbaldehyde derivative 3 was utilized as a starting material for the preparation of the new pyarazole derivatives. These target compounds were screened for their cytotoxic activity against MCF-7 followed by study cell cycle of the most active compounds. Finally, pharmacophore modeling and QSAR Studies was carried out.

Results: Among these compounds; 5d and 8b showed the highest anti-proliferative activity (IC50 = 4.9 and 2.11 µM, respectively). Flow cytometric analysis showed that, compounds 5d and 8b arrested the cell cycle in addition to induction of apoptosis in MCF7 cells. Moreover, their stimulation effect on caspases 3/7 was examined to explore their mechanism of induction of apoptosis and the results showed that their proapoptotic activity could be due to the activation of caspases 3/7.

Conclusion: Pyrazole derivatives 5d and 8b displayed potent bioactivities, indicating that these compounds could be considered as a new lead for more investigation in the future.

Keywords: 1, 3, 4-triaryl pyrazole, breast cancer, cell cycle analysis, apoptosis, caspase 3/7, QSAR study.

Graphical Abstract