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

Abstract

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.