Synthesis of a new series of 4-pyrazolylquinolinones with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors†

Abstract

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a–j) with apoptotic antiproliferative effects as dual EGFR/BRAF^V600E inhibitors were designed and synthesized. Compounds 5a–j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a–j demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a–j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI₅₀ values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI₅₀ = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAF^V600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAF^V600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAF^V600E, with high docking scores of −8.55 kcal mol⁻¹ and −8.22 kcal mol⁻¹, respectively. Furthermore, the ADME analysis of compounds 5a–j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.