Synthesis, antiproliferative and enzymatic inhibition activities of quinazolines incorporating benzenesulfonamide: Cell cycle analysis and molecular modeling study

Abstract

The antiproliferative activity of the synthesized quinazolines 2–22 was evaluated using NCI 60-human tumor cell lines. Quinazoline derivatives 5–8, 11, 14, 15, and 17–22 possessed potential antiproliferative activities against the tested cell lines with positive cytotoxic effects (PCE); 42/59–59/59, and median growth inhibition percentage (MGI%); 22–82%. Among the tested compounds, derivatives 14, 20, and 21 were the most active antiproliferative agents (MG_MID GI50; 2.13, 3.54, 2.29 μM, respectively), compared to erlotinib and gefitinib (MG_MID GI50; 7.68 and 2.10 μM, respectively). Quinazolines 5, 14, 18, and 20 exhibited strong EGFR inhibition activity (IC50; 74.41–100.17 nM), compared to gefitinib and erlotinib (IC50; 53.12 and 105.6 nM, respectively). Whereas derivatives 9, 14, and 20 possessed potent HER2 inhibition activity (IC50; 51.35–62.87 nM), compared to erlotinib (IC50; 85.93 nM). Derivatives 7, 9, and 14 revealed the highest inhibitory activity against COX-2 (IC50; 1.75- 4.12 μM) compared to celecoxib (IC50; 2.79 μM). Molecular docking studies of compound 14 with EGFR, HER2, and COX-2 were performed to generate the binding mode of interactions within the putative pockets.