A novel series of pyrano-quinoline compounds 5a–l was designed, synthesized, and investigated for
antiproliferative efficacy as multi-EGFR/HER-2/BRAFV600E 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 mM. 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 GI50 values of 26 and 28 nM, respectively, making
them more efficient than erlotinib (GI50 = 33 nM). Inhibitory assays on EGFR, HER-2, and BRAFV600E
indicated that compounds 5e and 5h were the most efficacious derivatives, with IC50 values of 71 nM
(EGFR), 62 nM (BRAFV600E), and 21 nM (HER-2) for compound 5e, whereas compound 5h displayed IC50
values of 75 nM (EGFR), 67 nM (BRAFV600E), and 23 nM (HER-2). Molecular 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, p–p stacking, and hydrophobic interactions, supporting its potential as a kinase inhibitor for
cancer treatment.