Molecular Docking, Dynamics, and Cytotoxicity Assessment of Pyrazolo[1,5‐ <i>a</i> ]pyrimidine Derivatives Against Breast Cancer

A number of pyrazolo[1,5-a]pyrimidine derivatives were effectively synthesized and described in this work and their biological activity has been checked against MCF-7, breast cancer cell line. All synthesized compounds were confirmed by mass and ¹H and ¹³C NMR spectroscopic techniques. In addition, the molecular docking of these compounds was performed against aromatase (PDB: 3EQM), a breast cancer target. According to the findings of molecular docking experiments, compounds 2 and 11 displayed greater binding affinities in comparison to the reference medications letrozole and exemestane. The docking scores for these compounds were -7.541 and -7.934 kcal/mol, respectively. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis provided further evidence that these interactions are stable. Molecular dynamics (MD) simulations provided further confirmation of this stability. The in vitro cytotoxicity experiments conducted on the MCF-7 breast cancer cell line revealed that compounds 2 and 11 had noteworthy anticancer activity. The average inhibitory concentration (IC₅₀) values for these compounds were 21.49 ± 1.59 and 22.68 ± 3.25 µM, respectively. When compared to the values of doxorubicin (23.88 ± 2.74 µM) and letrozole (38.45 ± 3.78 µM), these values were found to be comparable, indicating that they had a great potential to inhibit cancer. Based on the data, it appears that pyrazolo[1,5-a]pyrimidine derivatives have the potential to be effective lead candidates for the treatment of breast cancer by targeting aromatase inhibition. It is necessary to do more preclinical and clinical research to investigate the therapeutic potential of these proteins and their mechanism of action in the treatment of breast cancer.