Design, synthesis, antiproliferative activity, and molecular dynamics simulation of pyrazoline-based derivatives as dual EGFR and HER-2 inhibitors

The dual targeting of EGFR and HER2 is an established anticancer strategy. A novel series including two distinct scaffolds, A (chalcone-based compounds, 4a-n) and B (pyrazoline-based compounds, 5a-n), was developed and synthesized. The antiproliferative efficacy of 4a-n and 5a-n was examined against a panel of four cancer cell lines. The findings indicated that pyrazoline derivatives 5a-n exhibited more efficacy than chalcone compounds 4a-n. Compounds 4n, 5d, and 5g were identified as the most effective antiproliferative derivatives. These compounds were further investigated as dual EGFR/Her2 inhibitors. Compound 5d inhibited EGFR-TK and HER2 significantly, with IC₅₀ values of 0.126 and 0.061 μM, respectively. Moreover, compound 5d can induce a percentage of pre-G1 apoptosis by 78.53% in cell cycle analysis and cause early apoptosis with necrosis percent of 5.28. Docking and MD simulation illustrated the significant cytotoxic activity of the 5d compound and how it can be a promising scaffold with anticancer activity.