Synthesis of a new series of 4-pyrazolylquinolinones with apoptotic antiproliferative effects as dual EGFR/BRAF V600E inhibitors.

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 GI ₅₀ values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI ₅₀ = 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.
Competing Interests: The authors reported no potential conflicts of interest(s).
(This journal is © The Royal Society of Chemistry.)