Microwave-assisted synthesis of 2,5-dioxo-pyrano[3,2-c]quinoline-3-carboxylates and their investigation as antiproliferative agents targeting EGFR and/or BRAF^V600E

Pyrano[3,2-c]quinoline-3-carboxylate derivatives 3a-j were synthesized efficiently by the microwave–irradiated condensation of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes 4a-j with ethyl cyanoacetate (2) in the presence of ethanol and a catalytic amount of piperidine. The structures of the products were confirmed by a combination of spectral techniques including infra-red (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and elemental analyses in addition to X-ray structure analysis. The synthesized compounds 3a-j were tested for their in vitro antiproliferative activity against four human cancer cell lines using the MTT assay and doxorubicin as the reference drug: pancreas (Panc-1) cancer cell line, breast cancer (MCF-7) cell line, colon cancer (HT-29) cell line, and epithelial cancer (A-549) cell line. In comparison to the standard doxorubicin (GI₅₀= 1.10 µM), compounds 3a-j demonstrated promising antiproliferative action, with GI₅₀ values ranging from 1.30 to 5.90 µM. The most effective derivatives were compounds 3c, 3g, 3h, and 3i with GI₅₀ values ranging from 1.30 to 2.20 µM. The most potent antiproliferative derivative, compound 3c (R¹= OCH₃, R²= R³= H), was also the most potent EGFR inhibitor, with an IC₅₀ value of 105 ± 08 nM, 1.3-fold less potent than erlotinib (IC₅₀ = 80 ± 05 nM). Compounds 3g (R¹= Br, R²= R³= H) and 3h (R¹= Cl, R²= R³= H) were the second and third most active, with IC₅₀ values of 124 ± 10 nM and 195 ± 13 nM, respectively. Molecular docking calculations were conducted to inspect the docking scores and poses of the most promising compounds against EGFR and BRAF^V600E. Based on the docking computations, compounds 3c and 3g revealed promising docking scores against the EGFR and BRAF^V600E with values of − 7.9 and − 8.3 kcal/mol, respectively. Graphical Abstract: (Figure presented.)