Synthesis, cytotoxic evaluation, and molecular docking studies of novel quinazoline derivatives with benzenesulfonamide and anilide tails: Dual inhibitors of EGFR/HER2

Abstract

We synthesized a new series of 2-[(3-(4-sulfamoylphenethyl)-4(3H)-quinazolinon-2-yl)thio]anilide derivatives (2-16) and evaluated their cytotoxic activity against breast adenocarcinoma (MCF-7), colorectal adenocarcinoma (HT-29), and acute myeloid leukemia (HL-60 and K562) cells. To reveal their selectivity toward cancer cells, the compounds were also tested against the human fibroblast cell line, MRC-5. Compounds 1-5 exhibited potent cytotoxic activity against the tested cell lines with IC₅₀ values of 0.65-3.86, 0.68-4.60, 0.41-1.45, 0.42-4.07, and 3.77-25.55 μM, respectively compared to sorafenib, the standard drug (IC₅₀ 2.50, 2.50, and 3.14 μM against MCF-7, HT-29, and HL60 cells, respectively). Interestingly, compounds 1-5 displayed selectivity toward the cancer cell lines over MRC-5 (IC₅₀ 3.77-25.55 μM). These compounds also displayed potent inhibitory activity against EGFR and HER2 kinases (IC₅₀ 0.09-0.43 and 0.15-0.33 μM, respectively) compared to the standard drug, sorafenib (IC₅₀ 0.11 and 0.13 μM, respectively). Likewise, compounds 1, 4, and 5 showed strong inhibitory activity against VEGFR2 (IC₅₀ 0.34, 0.28 and 0.39 μM, respectively) compared to sorafenib (IC₅₀ 0.17 μM). We also employed molecular docking to identify the structural features required for the EGFR/HER2 inhibitory activity of the new series. Ultimately, compounds 1, 4, and 5 were demonstrated to be candidates for further preclinical investigations.

Keywords: Anticancer; EGFR; HER2; Molecular docking; Quinazolin-4-ones.