Design, synthesis, and antiproliferative activity of new 2-amino-pyrano[3,2- c ]quinoline-3-carbonitriles as potential EGFR, BRAF$^{V600E}$, and HER-2 inhibitors

A novel series of pyrano-quinoline compounds 5a–l was designed, synthesized, and investigated for antiproliferative efficacy as multi-EGFR/HER-2/BRAF$^{V600E}$ inhibitors. This work addresses the reaction between 4-hydroxy-2-oxo-1,2-dihydroquinolines and 2-benzylidenemalononitriles, which produces a new series of 2-amino-5-oxo-4-phenyl-5,6-dihydro-4H-pyrano[3,2-c]quinoline-3-carbonitrile derivatives 5a–l, giving good yields. The suggested mechanism was considered. The structures of 5a–l were elucidated using NMR spectroscopy, mass spectrometry, and elemental analysis. The cell viability assay of 5a–l against a normal cell line showed that none of the studied compounds exhibited cytotoxicity, and all hybrids retained above 90% cell viability at a dose of 50 μM. The antiproliferative activity of 5a–l was assessed against a panel of four cancer cell lines using the MTT assay. Compounds 5e and 5h had the most antiproliferative activity, with GI$_{50}$ values of 26 and 28 nM, respectively, making them more efficient than erlotinib (GI$_{50}$ = 33 nM). Inhibitory assays on EGFR, HER-2, and BRAF$^{V600E}$ indicated that compounds 5e and 5h were the most efficacious derivatives, with IC$_{50}$ values of 71 nM (EGFR), 62 nM (BRAFV600E), and 21 nM (HER-2) for compound 5e, whereas compound 5h displayed IC$_{50}$ values of 75 nM (EGFR), 67 nM (BRAF$^{V600E}$), and 23 nM (HER-2). ... mehrMolecular docking studies were conducted on a series of quinoline-based compounds to evaluate their binding affinity with EGFR and HER-2 kinases. Compound 5e showed promising interactions, forming stable complexes with key residues like Met769 (EGFR) and Asp863 (HER-2). The docking simulations revealed critical hydrogen bonding, π–π stacking, and hydrophobic interactions, supporting its potential as a kinase inhibitor for cancer treatment.