Some new Bis-pyrazoline hybrids 8–17 with dual EGFR and BRAFV600E inhibitors have
been developed. The target compounds were synthesized and tested in vitro against four cancer
cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values
of 1.05 M, 1.50 M, and 1.20 M, respectively. Hybrids showed dual inhibition of EGFR and
BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising
anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and
BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and
resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that
compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in
silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and
adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The
values of the HOMO and LUMO energies, as well as softness and hardness, were computationally
investigated using the DFT method. These findings agreed well with those of the in vitro research
and molecular docking study