Design, Synthesis, Antiproliferative Actions, and DFT Studies of NewBis-PyrazolineDerivatives asDual EGFR/BRAFV600E Inhibitors

Some new Bis-pyrazoline hybrids 8-17 with dual EGFR and BRAF(V600E) 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 GI(50) values of 1.05 mu M, 1.50 mu M, and 1.20 mu 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.

Automated summary

New Bis-pyrazoline hybrids 8-17 with dual EGFR and BRAF(V600E) inhibitors were developed and tested against four cancer cell lines in vitro. Compounds 12, 15, and 17 showed strong antiproliferative activity with GI(50) values of 1.05 μM, 1.50 μM, and 1.20 μM, respectively. These hybrids demonstrated dual inhibition of EGFR and BRAFV600E and exhibited promising anticancer activity, especially compound 12. Molecular docking studies supported their potential as dual EGFR/BRAFV600E inhibitors. Additionally, in silico ADMET prediction revealed low toxicity and adverse effects of the synthesized bis-pyrazoline hybrids.