Design, synthesis, and structural elucidation of ethyl 2-amino-5-oxo-4-aryl-4H-pyrano[3,2-c]quinoline-3-carboxylates as dual EGFR/HER-2 inhibitors endowed with antiproliferative activity

Abstract

A new series of quinoline-3-carboxylate derivatives 3a–k were developed as prospective dual inhibitors of EGFR and HER-2. Structural elucidation was accomplished via ¹H NMR, ¹³C NMR, DEPT NMR, elemental analysis and mass spectrometry. The synthesized compounds were evaluated for antiproliferative activity against breast (MCF-7) and colon (HT-29) cancer cell lines. Compounds 3a and 3f had the highest antiproliferative efficacy, especially against HT-29 colon cancer cells (IC₅₀ = 23 and 25 nM, respectively), surpassing erlotinib (IC₅₀ = 30 nM). Kinase inhibition experiments further validated the dual action of 3a and 3f, yielding IC₅₀ values of 68 nM and 30 nM against EGFR and HER-2, respectively, for 3a and IC₅₀ values of 71 and 33 nM against the same two kinases for 3f. Compounds 3a and 3f induced apoptosis by the activation of caspases 3, 8, and 9, alongside the overexpression of Bax and the downregulation of Bcl-2. In silico molecular docking studies were performed to investigate the binding interactions of the most active compound, 3a, with EGFR and HER-2 kinase domains. The compound showed strong binding affinities, forming critical hydrogen bonds and hydrophobic interactions with key active-site residues. Additionally, SwissADME analysis of 3a revealed full compliance with major drug-likeness filters, highlighting its potential as an orally available, dual EGFR/HER-2 inhibitor with favorable pharmacokinetic properties.