An innovative approach to development of new pyrazolylquinolin-2-one hybrids as dual EGFR and BRAFV600E inhibitors

• DOI: 10.1007/s11030-025-11127-4
• Publication Date: 2025-03-08T07:31:41Z
• Authors: Mohamed M. Hawwas; Ahmed S. Mancy; Mohamed Ramadan; Tarek S. Ibrahim; Ashraf H. Bayoumi; Mohamed Alswah

Abstract Novel quinoline-based derivatives 2a–e and 4a–j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d–g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC50 values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d–g were evaluated for their inhibitory activity on EGFR and BRAFV600E. Compound 4e exhibited the highest inhibitory activities, with IC50 values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAFV600E, compared to the reference drugs erlotinib (IC50 0.06 ± 0.002 μM) and vemurafenib (IC50 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d–g with respect to EGFR and BRAFV600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAFV600E compared to the reference drugs with values of − 3.226 and − 3.474 kcal/mol, respectively.